Gene products differentially expressed in cancerous cells and their methods of use II

ABSTRACT

The present invention provides polynucleotides, as well as polypeptides encoded thereby, that are differentially expressed in cancer cells. These polynucleotides are useful in a variety of diagnostic and therapeutic methods. The present invention further provides methods of reducing growth of cancer cells. These methods are useful for treating cancer.

SEQUENCE LISTING AND TABLES

A Sequence Listing is provided as part of this specification on triplicate compact discs, filed concurrently herewith, which compact discs named “Copy 1”, “Copy 2”, and “CRF” each of which compact discs contain the following file: “SEQLIST.TXT”, created Feb. 10, 2004, of 18 Megabytes, which is incorporated herein by reference in its entirety.

The present application also incorporates by reference Tables 2, 17, 18, 41A, 41B, 70A, 70B, 83, 84, 85, 86, 106, 107A, 107B, 110, 114, 130, 131A, 131B, 133, 134, 141, 143, 151 and 162 contained on duplicate compact discs filed concurrently herewith, which compact discs are labeled “Atty Docket 21302.001 Tables Copy 1” and “Atty Docket 21302.001 Tables Copy 2”. The details of these Tables are further described later in this disclosure. These compact discs were created on Feb. 10, 2004. The sizes of the Tables are as follows: Table 2: 147 kilobytes; Table 17: 344 kilobytes; Table 18: 372 kilobytes; Table 41A: 98 kilobytes; Table 41B: 41 kilobytes; Table 70A: 90 kilobytes; Table 70B: 72 kilobytes; Table 83: 60 kilobytes; Table 84: 94 kilobytes; Table 85: 251 kilobytes; Table 86: 232 kilobytes; Table 106: 148 kilobytes; Table 107A: 193 kilobytes; Table 107B: 138 kilobytes; Table 110: 278 kilobytes; Table 114: 11 kilobytes; Table 130: 395 kilobytes; Table 131A: 569 kilobytes; Table 131B: 354 kilobytes; Table 133: 40 kilobytes; Table 134: 8 kilobytes; Table 141: 402 kilobytes; Table 143: 98 kilobytes; Table 151: 8 kilobytes; and Table 162: 684 kilobytes.

LENGTHY TABLES The patent contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US08101349B2). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

FIELD OF THE INVENTION

The present invention relates to polynucleotides of human origin in substantially isolated form and gene products that are differentially expressed in cancer cells, and uses thereof.

BACKGROUND OF THE INVENTION

Cancer, like many diseases, is not the result of a single, well-defined cause, but rather can be viewed as several diseases, each caused by different aberrations in informational pathways, that ultimately result in apparently similar pathologic phenotypes. Identification of polynucleotides that correspond to genes that are differentially expressed in cancerous, pre-cancerous, or low metastatic potential cells relative to normal cells of the same tissue type, provides the basis for diagnostic tools, facilitates drug discovery by providing for targets for candidate agents, and further serves to identify therapeutic targets for cancer therapies that are more tailored for the type of cancer to be treated.

Identification of differentially expressed gene products also furthers the understanding of the progression and nature of complex diseases such as cancer, and is key to identifying the genetic factors that are responsible for the phenotypes associated with development of, for example, the metastatic phenotype. Identification of gene products that are differentially expressed at various stages, and in various types of cancers, can both provide for early diagnostic tests, and further serve as therapeutic targets. Additionally, the product of a differentially expressed gene can be the basis for screening assays to identify chemotherapeutic agents that modulate its activity (e.g. its expression, biological activity, and the like).

Early disease diagnosis is of central importance to halting disease progression, and reducing morbidity. Analysis of a patient's tumor to identify the gene products that are differentially expressed, and administration of therapeutic agent(s) designed to modulate the activity of those differentially expressed gene products, provides the basis for more specific, rational cancer therapy that may result in diminished adverse side effects relative to conventional therapies. Furthermore, confirmation that a tumor poses less risk to the patient (e.g., that the tumor is benign) can avoid unnecessary therapies. In short, identification of genes and the encoded gene products that are differentially expressed in cancerous cells can provide the basis of therapeutics, diagnostics, prognostics, therametrics, and the like.

For example, breast cancer is a leading cause of death among women. One of the priorities in breast cancer research is the discovery of new biochemical markers that can be used for diagnosis, prognosis and monitoring of breast cancer. The prognostic usefulness of these markers depends on the ability of the marker to distinguish between patients with breast cancer who require aggressive therapeutic treatment and patients who should be monitored.

While the pathogenesis of breast cancer is unclear, transformation of non-tumorigenic breast epithelium to a malignant phenotype may be the result of genetic factors, especially in women under 30 (Miki, et al., Science, 266: 66-71, 1994). However, it is likely that other, non-genetic factors are also significant in the etiology of the disease. Regardless of its origin, breast cancer morbidity increases significantly if a lesion is not detected early in its progression. Thus, considerable effort has focused on the elucidation of early cellular events surrounding transformation in breast tissue. Such effort has led to the identification of several potential breast cancer markers.

Thus, the identification of new markers associated with cancer, for example, breast cancer, and the identification of genes involved in transforming cells into the cancerous phenotype, remains a significant goal in the management of this disease. In exemplary aspects, the invention described herein provides cancer diagnostics, prognostics, therametrics, and therapeutics based upon polynucleotides and/or their encoded gene products.

SUMMARY OF THE INVENTION

The present invention provides methods and compositions useful in detection of cancerous cells, identification of agents that modulate the phenotype of cancerous cells, and identification of therapeutic targets for chemotherapy of cancerous cells. Cancerous, breast, colon and prostate cells are of particular interest in each of these aspects of the invention. More specifically, the invention provides polynucleotides in substantially isolated form, as well as polypeptides encoded thereby, that are differentially expressed in cancer cells. Also provided are antibodies that specifically bind the encoded polypeptides. These polynucleotides, polypeptides and antibodies are thus useful in a variety of diagnostic, therapeutic, and drug discovery methods. In some embodiments, a polynucleotide that is differentially expressed in cancer cells can be used in diagnostic assays to detect cancer cells. In other embodiments, a polynucleotide that is differentially expressed in cancer cells, and/or a polypeptide encoded thereby, is itself a target for therapeutic intervention.

Accordingly, the invention features an isolated polynucleotide comprising a nucleotide sequence having at least 90% sequence identity to an identifying sequence of any one of the sequences set forth herein or a degenerate variant thereof. In related aspects, the invention features recombinant host cells and vectors comprising the polynucleotides of the invention, as well as isolated polypeptides encoded by the polynucleotides of the invention and antibodies that specifically bind such polypeptides.

In other aspects, the invention provides a method for detecting a cancerous cell. In general, the method involves contacting a test sample obtained from a cell that is suspected of being a cancer cell with a probe for detecting a gene product differentially expressed in cancer. Many embodiments of the invention involve a gene identifiable by or comprising a sequence selected from the group consisting of SEQ ID NOS: 1-23767, contacting the probe and the gene product for a time sufficient for binding of the probe to the gene product; and comparing a level of binding of the probe to the sample with a level of probe binding to a control sample obtained from a control cell of known cancerous state. A modulated (i.e. increased or decreased) level of binding of the probe in the test cell sample relative to the level of binding in a control sample is indicative of the cancerous state of the test cell. In certain embodiments, the level of binding of the probe in the test cell sample, usually in relation to at least one control gene, is similar to binding of the probe to a cancerous cell sample. In certain other embodiments, the level of binding of the probe in the test cell sample, usually in relation to at least one control gene, is different, i.e. opposite, to binding of the probe to a non-cancerous cell sample. In specific embodiments, the probe is a polynucleotide probe and the gene product is nucleic acid. In other specific embodiments, the gene product is a polypeptide. In further embodiments, the gene product or the probe is immobilized on an array.

In another aspect, the invention provides a method for assessing the cancerous phenotype (e.g., metastasis, metastatic potential, aberrant cellular proliferation, and the like) of a cell comprising detecting expression of a gene product in a test cell sample, wherein the gene comprises or is identifiable using a sequence selected from the group consisting of SEQ ID NOS: 1-23767; and comparing a level of expression of the gene product in the test cell sample with a level of expression of the gene in a control cell sample. Comparison of the level of expression of the gene in the test cell sample relative to the level of expression in the control cell sample is indicative of the cancerous phenotype of the test cell sample. In specific embodiments, detection of gene expression is by detecting a level of an RNA transcript in the test cell sample. In other specific embodiments detection of expression of the gene is by detecting a level of a polypeptide in a test sample.

In another aspect, the invention provides a method for suppressing or inhibiting a cancerous phenotype of a cancerous cell, the method comprising introducing into a mammalian cell an expression modulatory agent (e.g. an antisense molecule, small molecule, antibody, neutralizing antibody, inhibitory RNA molecule, etc.) to inhibit expression of a gene identified by a sequence selected from the group consisting of SEQ ID NOS: 1-23767. Inhibition of expression of the gene inhibits development of a cancerous phenotype in the cell. In specific embodiments, the cancerous phenotype is metastasis, aberrant cellular proliferation relative to a normal cell, or loss of contact inhibition of cell growth. In the context of this invention “expression” of a gene is intended to encompass the expression of an activity of a gene product, and, as such, inhibiting expression of a gene includes inhibiting the activity of a product of the gene.

In another aspect, the invention provides a method for assessing the tumor burden of a subject, the method comprising detecting a level of a differentially expressed gene product in a test sample from a subject suspected of or having a tumor, the differentially expressed gene product identified by or comprising a sequence selected from the group consisting of SEQ ID NOS: 1-23767. Detection of the level of the gene product in the test sample is indicative of the tumor burden in the subject.

In another aspect, the invention provides a method for identifying agents that modulate (i.e. increase or decrease) the biological activity of a gene product differentially expressed in a cancerous cell, the method comprising contacting a candidate agent with a differentially expressed gene product, the differentially expressed gene product corresponding to a sequence selected from the group consisting of SEQ ID NOS: 1-23767; and detecting a modulation in a biological activity of the gene product relative to a level of biological activity of the gene product in the absence of the candidate agent. In specific embodiments, the detecting is by identifying an increase or decrease in expression of the differentially expressed gene product. In other specific embodiments, the gene product is mRNA or cDNA prepared from the mRNA gene product. In further embodiments, the gene product is a polypeptide.

In another aspect, the invention provides a method of inhibiting growth of a tumor cell by modulating expression of a gene product, where the gene product is encoded by a gene identified by a sequence selected from the group consisting of: SEQ ID NOS:1-23767.

These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1B is a comparison of SEQ ID NO:15951 and clone H72034 (SEQ ID NO:15983).

FIG. 2 is a comparison of SEQ ID NO:15982 and clone AA707002 (SEQ ID NO:15984).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides polynucleotides, as well as polypeptides encoded thereby, that are differentially expressed in cancer cells. Methods are provided in which these polynucleotides and polypeptides are used for detecting and reducing the growth of cancer cells. Also provided are methods in which the polynucleotides and polypeptides of the invention are used in a variety of diagnostic and therapeutic applications for cancer. The invention finds use in the prevention, treatment, detection or research into any cancer, including prostrate, pancreas, colon, brain, lung, breast, bone, skin cancers, etc.

Before the present invention is described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications and patent applications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a polynucleotide” includes a plurality of such polynucleotides and reference to “the cancer cell” includes reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.

The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

Definitions

The terms “polynucleotide” and “nucleic acid”, used interchangeably herein, refer to polymeric forms of nucleotides of any length, either ribonucleotides or deoxynucleotides. Thus, these terms include, but are not limited to, single-, double-, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. These terms further include, but are not limited to, mRNA or cDNA that comprise intronic sequences (see, e.g., Niwa et al. (1999) Cell 99(7):691-702). The backbone of the polynucleotide can comprise sugars and phosphate groups (as may typically be found in RNA or DNA), or modified or substituted sugar or phosphate groups. Alternatively, the backbone of the polynucleotide can comprise a polymer of synthetic subunits such as phosphoramidites and thus can be an oligodeoxynucleoside phosphoramidate or a mixed phosphoramidate-phosphodiester oligomer. Peyrottes et al. (1996) Nucl. Acids Res. 24:1841-1848; Chaturvedi et al. (1996) Nucl. Acids Res. 24:2318-2323. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, uracyl, other sugars, and linking groups such as fluororibose and thioate, and nucleotide branches. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications included in this definition are caps, substitution of one or more of the naturally occurring nucleotides with an analog, and introduction of means for attaching the polynucleotide to proteins, metal ions, labeling components, other polynucleotides, or a solid support. The term “polynucleotide” also encompasses peptidic nucleic acids (Pooga et al Curr Cancer Drug Targets. (2001) 1:231-9).

A “gene product” is a biopolymeric product that is expressed or produced by a gene. A gene product may be, for example, an unspliced RNA, an mRNA, a splice variant mRNA, a polypeptide, a post-translationally modified polypeptide, a splice variant polypeptide etc. Also encompassed by this term is biopolymeric products that are made using an RNA gene product as a template (i.e. cDNA of the RNA). A gene product may be made enzymatically, recombinantly, chemically, or within a cell to which the gene is native. In many embodiments, if the gene product is proteinaceous, it exhibits a biological activity. In many embodiments, if the gene product is a nucleic acid, it can be translated into a proteinaceous gene product that exhibits a biological activity.

A composition (e.g. a polynucleotide, polypeptide, antibody, or host cell) that is “isolated” or “in substantially isolated form” refers to a composition that is in an environment different from that in which the composition naturally occurs. For example, a polynucleotide that is in substantially isolated form is outside of the host cell in which the polynucleotide naturally occurs, and could be a purified fragment of DNA, could be part of a heterologous vector, or could be contained within a host cell that is not a host cell from which the polynucleotide naturally occurs. The term “isolated” does not refer to a genomic or cDNA library, whole cell total protein or mRNA preparation, genomic DNA preparation, or an isolated human chromosome. A composition which is in substantially isolated form is usually substantially purified.

As used herein, the term “substantially purified” refers to a compound (e.g., a polynucleotide, a polypeptide or an antibody, etc.) that is removed from its natural environment and is usually at least 60% free, preferably 75% free, and most preferably 90% free from other components with which it is naturally associated. Thus, for example, a composition containing A is “substantially free of” B when at least 85% by weight of the total A+B in the composition is A. Preferably, A comprises at least about 90% by weight of the total of A+B in the composition, more preferably at least about 95% or even 99% by weight. In the case of polynucleotides, “A” and “B” may be two different genes positioned on different chromosomes or adjacently on the same chromosome, or two isolated cDNA species, for example.

The terms “polypeptide” and “protein”, interchangeably used herein, refer to a polymeric form of amino acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. The term includes fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusions with heterologous and homologous leader sequences, with or without N-terminal methionine residues; immunologically tagged proteins; and the like.

“Heterologous” refers to materials that are derived from different sources (e.g., from different genes, different species, etc.).

As used herein, the terms “a gene that is differentially expressed in a cancer cell,” and “a polynucleotide that is differentially expressed in a cancer cell” are used interchangeably herein, and generally refer to a polynucleotide that represents or corresponds to a gene that is differentially expressed in a cancerous cell when compared with a cell of the same cell type that is not cancerous, e.g., mRNA is found at levels at least about 25%, at least about 50% to about 75%, at least about 90%, at least about 1.5-fold, at least about 2-fold, at least about 5-fold, at least about 10-fold, or at least about 50-fold or more, different (e.g., higher or lower). The comparison can be made in tissue, for example, if one is using in situ hybridization or another assay method that allows some degree of discrimination among cell types in the tissue. The comparison may also or alternatively be made between cells removed from their tissue source.

“Differentially expressed polynucleotide” as used herein refers to a nucleic acid molecule (RNA or DNA) comprising a sequence that represents a differentially expressed gene, e.g., the differentially expressed polynucleotide comprises a sequence (e.g., an open reading frame encoding a gene product; a non-coding sequence) that uniquely identifies a differentially expressed gene so that detection of the differentially expressed polynucleotide in a sample is correlated with the presence of a differentially expressed gene in a sample. “Differentially expressed polynucleotides” is also meant to encompass fragments of the disclosed polynucleotides, e.g., fragments retaining biological activity, as well as nucleic acids homologous, substantially similar, or substantially identical (e.g., having about 90% sequence identity) to the disclosed polynucleotides.

“Corresponds to” or “represents” when used in the context of, for example, a polynucleotide or sequence that “corresponds to” or “represents” a gene means that at least a portion of a sequence of the polynucleotide is present in the gene or in the nucleic acid gene product (e.g., mRNA or cDNA). A subject nucleic acid may also be “identified” by a polynucleotide if the polynucleotide corresponds to or represents the gene. Genes identified by a polynucleotide may have all or a portion of the identifying sequence wholly present within an exon of a genomic sequence of the gene, or different portions of the sequence of the polynucleotide may be present in different exons (e.g., such that the contiguous polynucleotide sequence is present in an mRNA, either pre- or post-splicing, that is an expression product of the gene). In some embodiments, the polynucleotide may represent or correspond to a gene that is modified in a cancerous cell relative to a normal cell. The gene in the cancerous cell may contain a deletion, insertion, substitution, or translocation relative to the polynucleotide and may have altered regulatory sequences, or may encode a splice variant gene product, for example. The gene in the cancerous cell may be modified by insertion of an endogenous retrovirus, a transposable element, or other naturally occurring or non-naturally occurring nucleic acid. In most cases, a polynucleotide corresponds to or represents a gene if the sequence of the polynucleotide is most identical to the sequence of a gene or its product (e.g. mRNA or cDNA) as compared to other genes or their products. In most embodiments, the most identical gene is determined using a sequence comparison of a polynucleotide to a database of polynucleotides (e.g. GenBank) using the BLAST program at default settings For example, if the most similar gene in the human genome to an exemplary polynucleotide is the protein kinase C gene, the exemplary polynucleotide corresponds to protein kinase C. In most cases, the sequence of a fragment of an exemplary polynucleotide is at least 95%, 96%, 97%, 98%, 99% or up to 100% identical to a sequence of at least 15, 20, 25, 30, 35, 40, 45, or 50 contiguous nucleotides of a corresponding gene or its product (mRNA or cDNA), when nucleotides that are “N” represent G, A, T or C.

An “identifying sequence” is a minimal fragment of a sequence of contiguous nucleotides that uniquely identifies or defines a polynucleotide sequence or its complement. In many embodiments, a fragment of a polynucleotide uniquely identifies or defines a polynucleotide sequence or its complement. In some embodiments, the entire contiguous sequence of a gene, cDNA, EST, or other provided sequence is an identifying sequence.

“Diagnosis” as used herein generally includes determination of a subject's susceptibility to a disease or disorder, determination as to whether a subject is presently affected by a disease or disorder, prognosis of a subject affected by a disease or disorder (e.g., identification of pre-metastatic or metastatic cancerous states, stages of cancer, or responsiveness of cancer to therapy), and use of therametrics (e.g., monitoring a subject's condition to provide information as to the effect or efficacy of therapy).

As used herein, the term “a polypeptide associated with cancer” refers to a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell.

The term “biological sample” encompasses a variety of sample types obtained from an organism and can be used in a diagnostic or monitoring assay. The term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof. The term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components. The term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

The terms “treatment”, “treating”, “treat” and the like are used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. “Treatment” as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.

The terms “individual,” “subject,” “host,” and “patient,” used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. Other subjects may include cattle, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and the like.

A “host cell”, as used herein, refers to a microorganism or a eukaryotic cell or cell line cultured as a unicellular entity which can be, or has been, used as a recipient for a recombinant vector or other transfer polynucleotides, and include the progeny of the original cell which has been transfected. It is understood that the progeny of a single cell may not necessarily be completely identical in morphology or in genomic or total DNA complement as the original parent, due to natural, accidental, or deliberate mutation.

The terms “cancer”, “neoplasm”, “tumor”, and “carcinoma”, are used interchangeably herein to refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. Detection of cancerous cells is of particular interest.

The term “normal” as used in the context of “normal cell,” is meant to refer to a cell of an untransformed phenotype or exhibiting a morphology of a non-transformed cell of the tissue type being examined.

“Cancerous phenotype” generally refers to any of a variety of biological phenomena that are characteristic of a cancerous cell, which phenomena can vary with the type of cancer. The cancerous phenotype is generally identified by abnormalities in, for example, cell growth or proliferation (e.g., uncontrolled growth or proliferation), regulation of the cell cycle, cell mobility, cell-cell interaction, or metastasis, etc.

“Therapeutic target” generally refers to a gene or gene product that, upon modulation of its activity (e.g., by modulation of expression, biological activity, and the like), can provide for modulation of the cancerous phenotype.

As used throughout, “modulation” is meant to refer to an increase or a decrease in the indicated phenomenon (e.g., modulation of a biological activity refers to an increase in a biological activity or a decrease in a biological activity).

Polynucleotide Compositions

The present invention provides isolated polynucleotides that contain nucleic acids that are differentially expressed in cancer cells. The polynucleotides, as well as any polypeptides encoded thereby, find use in a variety of therapeutic and diagnostic methods.

The scope of the invention with respect to compositions containing the isolated polynucleotides useful in the methods described herein includes, but is not necessarily limited to, polynucleotides having (i.e., comprising) a sequence set forth in any one of the polynucleotide sequences provided herein, or fragment thereof, polynucleotides obtained from the biological materials described herein or other biological sources (particularly human sources) by hybridization under stringent conditions (particularly conditions of high stringency); genes corresponding to the provided polynucleotides; cDNAs corresponding to the provided polynucleotides; variants of the provided polynucleotides and their corresponding genes, particularly those variants that retain a biological activity of the encoded gene product (e.g., a biological activity ascribed to a gene product corresponding to the provided polynucleotides as a result of the assignment of the gene product to a protein family(ies) and/or identification of a functional domain present in the gene product). Other nucleic acid compositions contemplated by and within the scope of the present invention will be readily apparent to one of ordinary skill in the art when provided with the disclosure here. “Polynucleotide” and “nucleic acid” as used herein with reference to nucleic acids of the composition is not intended to be limiting as to the length or structure of the nucleic acid unless specifically indicated.

The invention features polynucleotides that represent genes that are expressed in human tissue, specifically polynucleotides that are differentially expressed in tissues containing cancerous cells. Nucleic acid compositions described herein of particular interest are at least about 15 bp in length, at least about 30 bp in length, at least about 50 bp in length, at least about 100 bp, at least about 200 bp in length, at least about 300 bp in length, at least about 500 bp in length, at least about 800 bp in length, at least about 1 kb in length, at least about 2.0 kb in length, at least about 3.0 kb in length, at least about 5 kb in length, at least about 10 kb in length, at least about 50 kb in length and are usually less than about 200 kb in length. These polynucleotides (or polynucleotide fragments) have uses that include, but are not limited to, diagnostic probes and primers as starting materials for probes and primers, as discussed herein.

The subject polynucleotides usually comprise a sequence set forth in any one of the polynucleotide sequences provided herein, for example, in the sequence listing, incorporated by reference in a table (e.g. by an NCBI accession number), a cDNA deposited at the A.T.C.C., or a fragment or variant thereof. A “fragment” or “portion” of a polynucleotide is a contiguous sequence of residues at least about 10 nt to about 12 nt, 15 nt, 16 nt, 18 nt or 20 nt in length, usually at least about 22 nt, 24 nt, 25 nt, 30 nt, 40 nt, 50 nt, 60 nt, 70 nt, 80 nt, 90 nt, 100 nt to at least about 150 nt, 200 nt, 250 nt, 300 nt, 350 nt, 400 nt, 500 nt, 800 nt or up to about 1000 nt, 1500 or 2000 nt in length. In some embodiments, a fragment of a polynucleotide is the coding sequence of a polynucleotide. A fragment of a polynucleotide may start at position 1 (i.e. the first nucleotide) of a nucleotide sequence provided herein, or may start at about position 10, 20, 30, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500 or 2000, or an ATG translational initiation codon of a nucleotide sequence provided herein. In this context “about” includes the particularly recited value or a value larger or smaller by several (5, 4, 3, 2, or 1) nucleotides. The described polynucleotides and fragments thereof find use as hybridization probes, PCR primers, BLAST probes, or as an identifying sequence, for example.

The subject nucleic acids may be variants or degenerate variants of a sequence provided herein. In general, a variants of a polynucleotide provided herein have a fragment of sequence identity that is greater than at least about 65%, greater than at least about 70%, greater than at least about 75%, greater than at least about 80%, greater than at least about 85%, or greater than at least about 90%, 95%, 96%, 97%, 98%, 99% or more (i.e. 100%) as compared to an identically sized fragment of a provided sequence. as determined by the Smith-Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular). For the purposes of this invention, a preferred method of calculating percent identity is the Smith-Waterman algorithm. Global DNA sequence identity should be greater than 65% as determined by the Smith-Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular) using an gap search with the following search parameters: gap open penalty, 12; and gap extension penalty, 1.

The subject nucleic acid compositions include full-length cDNAs or mRNAs that encompass an identifying sequence of contiguous nucleotides from any one of the polynucleotide sequences provided herein.

As discussed above, the polynucleotides useful in the methods described herein also include polynucleotide variants having sequence similarity or sequence identity. Nucleic acids having sequence similarity are detected by hybridization under low stringency conditions, for example, at 50° C. and 10×SSC (0.9 M saline/0.09 M sodium citrate) and remain bound when subjected to washing at 55° C. in 1×SSC. Sequence identity can be determined by hybridization under high stringency conditions, for example, at 50° C. or higher and 0.1×SSC (9 mM saline/0.9 mM sodium citrate). Hybridization methods and conditions are well known in the art, see, e.g., U.S. Pat. No. 5,707,829. Nucleic acids that are substantially identical to the provided polynucleotide sequences, e.g. allelic variants, genetically altered versions of the gene, etc., bind to the provided polynucleotide sequences under stringent hybridization conditions. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes can be any species, e.g. primate species, particularly human; rodents, such as rats and mice; canines, felines, bovines, ovines, equines, yeast, nematodes, etc.

In one embodiment, hybridization is performed using a fragment of at least 15 contiguous nucleotides (nt) of at least one of the polynucleotide sequences provided herein. That is, when at least 15 contiguous nt of one of the disclosed polynucleotide sequences is used as a probe, the probe will preferentially hybridize with a nucleic acid comprising the complementary sequence, allowing the identification and retrieval of the nucleic acids that uniquely hybridize to the selected probe. Probes from more than one polynucleotide sequence provided herein can hybridize with the same nucleic acid if the cDNA from which they were derived corresponds to one mRNA.

Polynucleotides contemplated for use in the invention also include those having a sequence of naturally occurring variants of the nucleotide sequences (e.g., degenerate variants (e.g., sequences that encode the same polypeptides but, due to the degenerate nature of the genetic code, different in nucleotide sequence), allelic variants, etc.). Variants of the polynucleotides contemplated by the invention are identified by hybridization of putative variants with nucleotide sequences disclosed herein, preferably by hybridization under stringent conditions. For example, by using appropriate wash conditions, variants of the polynucleotides described herein can be identified where the allelic variant exhibits at most about 25-30% base pair (bp) mismatches relative to the selected polynucleotide probe. In general, allelic variants contain 15-25% bp mismatches, and can contain as little as even 5-15%, or 2-5%, or 1-2% bp mismatches, as well as a single bp mismatch.

The invention also encompasses homologs corresponding to any one of the polynucleotide sequences provided herein, where the source of homologous genes can be any mammalian species, e.g., primate species, particularly human; rodents, such as rats; canines, felines, bovines, ovines, equines, yeast, nematodes, etc. Between mammalian species, e.g., human and mouse, homologs generally have substantial sequence similarity, e.g., at least 75% sequence identity, usually at least 80%%, at least 85, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or even 100% identity between nucleotide sequences. Sequence similarity is calculated based on a reference sequence, which may be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, etc. A reference sequence will usually be at least about a fragment of a polynucleotide sequence and may extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art, such as gapped BLAST, described in Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402, or TeraBLAST available from TimeLogic Corp. (Crystal Bay, Nev.).

The subject nucleic acids can be cDNAs or genomic DNAs, as well as fragments thereof, particularly fragments that encode a biologically active gene product and/or are useful in the methods disclosed herein (e.g., in diagnosis, as a unique identifier of a differentially expressed gene of interest, etc.). The term “cDNA” as used herein is intended to include all nucleic acids that share the arrangement of sequence elements found in native mature mRNA species, where sequence elements are exons and 3′ and 5′ non-coding regions. Normally mRNA species have contiguous exons, with the intervening introns, when present, being removed by nuclear RNA splicing, to create a continuous open reading frame encoding a polypeptide. mRNA species can also exist with both exons and introns, where the introns may be removed by alternative splicing. Furthermore it should be noted that different species of mRNAs encoded by the same genomic sequence can exist at varying levels in a cell, and detection of these various levels of mRNA species can be indicative of differential expression of the encoded gene product in the cell.

A genomic sequence of interest comprises the nucleic acid present between the initiation codon and the stop codon, as defined in the listed sequences, including all of the introns that are normally present in a native chromosome. It can further include the 3′ and 5′ untranslated regions found in the mature mRNA. It can further include specific transcriptional and translational regulatory sequences, such as promoters, enhancers, etc., including about 1 kb, but possibly more, of flanking genomic DNA at either the 5′ and 3′ end of the transcribed region. The genomic DNA can be isolated as a fragment of 100 kbp or smaller; and substantially free of flanking chromosomal sequence. The genomic DNA flanking the coding region, either 3′ and 5′, or internal regulatory sequences as sometimes found in introns, contains sequences required for proper tissue, stage-specific, or disease-state specific expression.

The nucleic acid compositions of the subject invention can encode all or a part of the naturally-occurring polypeptides. Double or single stranded fragments can be obtained from the DNA sequence by chemically synthesizing oligonucleotides in accordance with conventional methods, by restriction enzyme digestion, by PCR amplification, etc.

Probes specific to the polynucleotides described herein can be generated using the polynucleotide sequences disclosed herein. The probes are usually a fragment of a polynucleotide sequences provided herein. The probes can be synthesized chemically or can be generated from longer polynucleotides using restriction enzymes. The probes can be labeled, for example, with a radioactive, biotinylated, or fluorescent tag. Preferably, probes are designed based upon an identifying sequence of any one of the polynucleotide sequences provided herein. More preferably, probes are designed based on a contiguous sequence of one of the subject polynucleotides that remain unmasked following application of a masking program for masking low complexity (e.g., XBLAST, RepeatMasker, etc.) to the sequence, i.e., one would select an unmasked region, as indicated by the polynucleotides outside the poly-n stretches of the masked sequence produced by the masking program.

The polynucleotides of interest in the subject invention are isolated and obtained in substantial purity, generally as other than an intact chromosome. Usually, the polynucleotides, either as DNA or RNA, will be obtained substantially free of other naturally-occurring nucleic acid sequences that they are usually associated with, generally being at least about 50%, usually at least about 90% pure and are typically “recombinant”, e.g., flanked by one or more nucleotides with which it is not normally associated on a naturally occurring chromosome.

The polynucleotides described herein can be provided as a linear molecule or within a circular molecule, and can be provided within autonomously replicating molecules (vectors) or within molecules without replication sequences. Expression of the polynucleotides can be regulated by their own or by other regulatory sequences known in the art. The polynucleotides can be introduced into suitable host cells using a variety of techniques available in the art, such as transferrin polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated DNA transfer, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, gene gun, calcium phosphate-mediated transfection, and the like.

The nucleic acid compositions described herein can be used to, for example, produce polypeptides, as probes for the detection of mRNA in biological samples (e.g., extracts of human cells) or cDNA produced from such samples, to generate additional copies of the polynucleotides, to generate ribozymes or antisense oligonucleotides, and as single stranded DNA probes or as triple-strand forming oligonucleotides. The probes described herein can be used to, for example, determine the presence or absence of any one of the polynucleotide provided herein or variants thereof in a sample. These and other uses are described in more detail below.

Polypeptides and Variants Thereof

The present invention further provides polypeptides encoded by polynucleotides that represent genes that are differentially expressed in cancer cells. Such polypeptides are referred to herein as “polypeptides associated with cancer.” The polypeptides can be used to generate antibodies specific for a polypeptide associated with cancer, which antibodies are in turn useful in diagnostic methods, prognostics methods, therametric methods, and the like as discussed in more detail herein. Polypeptides are also useful as targets for therapeutic intervention, as discussed in more detail herein.

The polypeptides contemplated by the invention include those encoded by the disclosed polynucleotides and the genes to which these polynucleotides correspond, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed polynucleotides. Further polypeptides contemplated by the invention include polypeptides that are encoded by polynucleotides that hybridize to polynucleotide of the sequence listing. Thus, the invention includes within its scope a polypeptide encoded by a polynucleotide having the sequence of any one of the polynucleotide sequences provided herein, or a variant thereof.

In general, the term “polypeptide” as used herein refers to both the full length polypeptide encoded by the recited polynucleotide, the polypeptide encoded by the gene represented by the recited polynucleotide, as well as portions or fragments thereof. “Polypeptides” also includes variants of the naturally occurring proteins, where such variants are homologous or substantially similar to the naturally occurring protein, and can be of an origin of the same or different species as the naturally occurring protein (e.g., human, murine, or some other species that naturally expresses the recited polypeptide, usually a mammalian species). In general, variant polypeptides have a sequence that has at least about 80%, usually at least about 90%, and more usually at least about 98% sequence identity with a differentially expressed polypeptide described herein, as measured by BLAST 2.0 using the parameters described above. The variant polypeptides can be naturally or non-naturally glycosylated, i.e., the polypeptide has a glycosylation pattern that differs from the glycosylation pattern found in the corresponding naturally occurring protein.

The invention also encompasses homologs of the disclosed polypeptides (or fragments thereof) where the homologs are isolated from other species, i.e. other animal or plant species, where such homologs, usually mammalian species, e.g. rodents, such as mice, rats; domestic animals, e.g., horse, cow, dog, cat; and humans. By “homolog” is meant a polypeptide having at least about 35%, usually at least about 40% and more usually at least about 60% amino acid sequence identity to a particular differentially expressed protein as identified above, where sequence identity is determined using the BLAST 2.0 algorithm, with the parameters described supra.

In general, the polypeptides of interest in the subject invention are provided in a non-naturally occurring environment, e.g. are separated from their naturally occurring environment. In certain embodiments, the subject protein is present in a composition that is enriched for the protein as compared to a cell or extract of a cell that naturally produces the protein. As such, isolated polypeptide is provided, where by “isolated” or “in substantially isolated form” is meant that the protein is present in a composition that is substantially free of other polypeptides, where by substantially free is meant that less than 90%, usually less than 60% and more usually less than 50% of the composition is made up of other polypeptides of a cell that the protein is naturally found.

Also within the scope of the invention are variants; variants of polypeptides include mutants, fragments, and fusions. Mutants can include amino acid substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, a phosphorylation site or an acetylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Conservative amino acid substitutions are those that preserve the general charge, hydrophobicity/hydrophilicity, and/or steric bulk of the amino acid substituted.

Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain and/or, where the polypeptide is a member of a protein family, a region associated with a consensus sequence). For example, muteins can be made which are optimized for increased antigenicity, i.e. amino acid variants of a polypeptide may be made that increase the antigenicity of the polypeptide. Selection of amino acid alterations for production of variants can be based upon the accessibility (interior vs. exterior) of the amino acid (see, e.g., Go et al, Int. J. Peptide Protein Res. (1980) 15:211), the thermostability of the variant polypeptide (see, e.g., Querol et al., Prot. Eng. (1996) 9:265), desired glycosylation sites (see, e.g., Olsen and Thomsen, J. Gen. Microbiol. (1991) 137:579), desired disulfide bridges (see, e.g., Clarke et al., Biochemistry (1993) 32:4322; and Wakarchuk et al., Protein Eng. (1994) 7:1379), desired metal binding sites (see, e.g., Toma et al., Biochemistry (1991) 30:97, and Haezerbrouck et al., Protein Eng. (1993) 6:643), and desired substitutions with in proline loops (see, e.g., Masul et al., Appl. Env. Microbiol. (1994) 60:3579). Cysteine-depleted muteins can be produced as disclosed in U.S. Pat. No. 4,959,314. Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Fragments of interest will typically be at least about 10 aa to at least about 15 aa in length, usually at least about 50 aa in length, and can be as long as 300 aa in length or longer, but will usually not exceed about 1000 aa in length, where the fragment will have a stretch of amino acids that is identical to a polypeptide encoded by a polynucleotide having a sequence of any one of the polynucleotide sequences provided herein, or a homolog thereof. The protein variants described herein are encoded by polynucleotides that are within the scope of the invention. The genetic code can be used to select the appropriate codons to construct the corresponding variants.

A fragment of a subject polypeptide is, for example, a polypeptide having an amino acid sequence which is a portion of a subject polypeptide e.g. a polypeptide encoded by a subject polynucleotide that is identified by any one of the sequence of SEQ ID NOS 1-499 or its complement. The polypeptide fragments of the invention are preferably at least about 9 aa, at least about 15 aa, and more preferably at least about 20 aa, still more preferably at least about 30 aa, and even more preferably, at least about 40 aa, at least about 50 aa, at least about 75 aa, at least about 100 aa, at least about 125 aa or at least about 150 aa in length. A fragment “at least 20 aa in length,” for example, is intended to include 20 or more contiguous amino acids from, for example, the polypeptide encoded by a cDNA, in a cDNA clone contained in a deposited library, or a nucleotide sequence shown in SEQ ID NOS:1-23767 or the complementary stand thereof. In this context “about” includes the particularly recited value or a value larger or smaller by several (5, 4, 3, 2, or 1) amino acids. These polypeptide fragments have uses that include, but are not limited to, production of antibodies as discussed herein. Of course, larger fragments (e.g., at least 150, 175, 200, 250, 500, 600, 1000, or 2000 amino acids in length) are also encompassed by the invention.

Moreover, representative examples of polypeptides fragments of the invention (useful in, for example, as antigens for antibody production), include, for example, fragments comprising, or alternatively consisting of, a sequence from about amino acid number 1-10, 5-10, 10-20, 21-31, 31-40, 41-61, 61-81, 91-120, 121-140, 141-162, 162-200, 201-240, 241-280, 281-320, 321-360, 360-400, 400-450, 451-500, 500-600, 600-700, 700-800, 800-900 and the like. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) amino acids, at either terminus or at both termini. In some embodiments, these fragments has a functional activity (e.g., biological activity) whereas in other embodiments, these fragments may be used to make an antibody.

In one example, a polynucleotide having a sequence set forth in the sequence listing, containing no flanking sequences (i.e., consisting of the sequence set forth in the sequence listing), may be cloned into an expression vector having ATG and a stop codon (e.g. any one of the pET vector from Invitrogen, or other similar vectors from other manufactures), and used to express a polypeptide of interest encoded by the polynucleotide in a suitable cell, e.g., a bacterial cell. Accordingly, the polynucleotides may be used to produce polypeptides, and these polypeptides may be used to produce antibodies by known methods described above and below. In many embodiments, the sequence of the encoded polypeptide does not have to be known prior to its expression in a cell. However, if it desirable to know the sequence of the polypeptide, this may be derived from the sequence of the polynucleotide. Using the genetic code, the polynucleotide may be translated by hand, or by computer means. Suitable software for identifying open reading frames and translating them into polypeptide sequences are well know in the art, and include: Lasergene™ from DNAStar (Madison, Wis.), and Vector NTI™ from Informax (Frederick Md.), and the like.

Further polypeptide variants may are described in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429

Vectors, Host Cells and Protein Production

The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.

The polynucleotides of the invention may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.

As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418 or neomycin resistance for eukaryotic cell culture and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. coli and other bacteria.

Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris (ATCC Accession No. 201178)); insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. 5 Appropriate culture mediums and conditions for the above-described host cells are known in the art.

Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNHSA, pNH16a, pNH18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRITS available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Preferred expression vectors for use in yeast systems include, but are not limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, and PAO815 (all available from Invitrogen, Carload, Calif.). Other suitable vectors will be readily apparent to the skilled artisan.

Nucleic acids of interest may be cloned into a suitable vector by route methods. Suitable vectors include plasmids, cosmids, recombinant viral vectors e.g. retroviral vectors, YACs, BACs and the like, phage vectors.

Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.

A polypeptide of this invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification.

Polypeptides of the present invention can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host mediated processes. Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.

Suitable methods and compositions for polypeptide expression may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429, and suitable methods and compositions for production of modified polypeptides may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429.

Antibodies and Other Polypeptide or Polynucleotide Binding Molecules

The present invention further provides antibodies, which may be isolated antibodies, that are specific for a polypeptide encoded by a polynucleotide described herein and/or a polypeptide of a gene that corresponds to a polynucleotide described herein. Antibodies can be provided in a composition comprising the antibody and a buffer and/or a pharmaceutically acceptable excipient. Antibodies specific for a polypeptide associated with cancer are useful in a variety of diagnostic and therapeutic methods, as discussed in detail herein.

Gene products, including polypeptides, mRNA (particularly mRNAs having distinct secondary and/or tertiary structures), cDNA, or complete gene, can be prepared and used for raising antibodies for experimental, diagnostic, and therapeutic purposes. Antibodies may be used to identify a gene corresponding to a polynucleotide. The polynucleotide or related cDNA is expressed as described above, and antibodies are prepared. These antibodies are specific to an epitope on the polypeptide encoded by the polynucleotide, and can precipitate or bind to the corresponding native protein in a cell or tissue preparation or in a cell-free extract of an in vitro expression system.

Antibodies

Further polypeptides of the invention relate to antibodies and T-cell antigen receptors (TCR) which immunospecifically bind a subject polypeptide, subject polypeptide fragment, or variant thereof, and/or an epitope thereof (as determined by immunoassays well known in the art for assaying specific antibody-antigen binding). Antibodies of the invention include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′) fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), and epitope-binding fragments of any of the above. The term “antibody,” as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.

Most preferably the antibodies are human antigen-binding antibody fragments of the present invention and include, but are not limited to, Fab. Fab′ and F(ab′)₂, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a V_(L) or V_(H) domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, C_(H)1, C_(H)2, and C_(H)3 domains. Also included in the invention are antigen-binding fragments also comprising any combination of variable region(s) with a hinge region, C_(H)1, C_(H)2, and C_(H)3 domains. The antibodies of the invention may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from, human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulin and that do not express endogenous immunoglobulins, as described infra and, for example in, U.S. Pat. No. 5,939,598 by Kucherlapati et al.

The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol. 148:1547-1553 (1992).

Antibodies of the present invention may be described or specified in terms of the epitope(s) or portion(s) of a polypeptide of the present invention which they recognize or specifically bind. The epitope(s) or polypeptide portion(s) may be specified as described herein, e.g., by N-terminal and C-terminal positions, or by size in contiguous amino acid residues. Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded. Therefore, the present invention includes antibodies that specifically bind polypeptides of the present invention, and allows for the exclusion of the same.

Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not bind any other analog, ortholog, or homolog of a polypeptide of the present invention are included. Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In specific embodiments, antibodies of the present invention cross-react with murine, rat and/or rabbit homologs of human proteins and the corresponding epitopes thereof. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In a specific embodiment, the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combination(s) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein. Further included in the present invention are antibodies which bind polypeptides encoded by polynucleotides which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention. Preferred binding affinities include those with a dissociation constant or Kd less 5×10⁻⁵ M, 10⁻⁵ M, 5×10⁻⁶ M, 10⁻⁶ M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, 10⁻⁸ M, 5×10⁻⁹ M, 10⁻⁹ M, 5×10⁻¹⁰ M, 10−10 M, etc.

The invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of the invention as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein. In preferred embodiments, the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.

Methods for making screening, assaying, humanizing, and modifying different types of antibody are well known in the art and may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429.

In addition, the invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody of the invention and fragments thereof. The invention also encompasses polynucleotides that hybridize under stringent or alternatively, under lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a polypeptide of the invention, preferably, an antibody that binds to a subject polypeptide.

The antibodies of the invention can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques. Recombinant expression of an antibody of the invention, or fragment, derivative or analog thereof, (e.g., a heavy or light chain of an antibody of the invention or a single chain antibody of the invention), requires construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.

The expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody of the invention. Thus, the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody of the invention, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chained antibodies, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to express the antibody molecules of the invention. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).

Antibodies production is well known in the art. Exemplary methods and compositions for making antibodies may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429.

Immunophenotyping

The antibodies of the invention may be utilized for immunophenotyping of cell lines and biological samples. The translation product of the gene of the present invention may be useful as a cell specific marker, or more specifically as a cellular marker that is differentially expressed at various stages of differentiation and/or maturation of particular cell types. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No. 5,985,660; and Morrison et al. Cell, 96:737-49 (1999)).

These techniques allow for the screening of particular populations of cells, such as might be found with hematological malignancies (i.e. minimal residual disease (MRD) in acute leukemic patients) and “non-self cells in transplantations to prevent Graft-versus-Host Disease (GVHD). Alternatively, these techniques allow for the screening of hematopoietic stem and progenitor cells capable of undergoing proliferation and/or differentiation, as might be found in human umbilical cord blood.

Kits

Also provided by the subject invention are kits for practicing the subject methods, as described above. The subject kits include at least one or more of: a subject nucleic acid, isolated polypeptide or an antibody thereto. Other optional components of the kit include: restriction enzymes, control primers and plasmids; buffers, cells, carriers adjuvents etc. The nucleic acids of the kit may also have restrictions sites, multiple cloning sites, primer sites, etc to facilitate their ligation other plasmids. The various components of the kit may be present in separate containers or certain compatible components may be precombined into a single container, as desired. In many embodiments, kits with unit doses of the active agent, e.g. in oral or injectable doses, are provided. In certain embodiments, controls, such as samples from a cancerous or non-cancerous cell are provided by the invention. Further embodiments of the kit include an antibody for a subject polypeptide and a chemotherapeutic agent to be used in combination with the polypeptide as a treatment.

In addition to above-mentioned components, the subject kits typically further include instructions for using the components of the kit to practice the subject methods. The instructions for practicing the subject methods are generally recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or subpackaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.

Computer-Related Embodiments

In general, a library of polynucleotides is a collection of sequence information, which information is provided in either biochemical form (e.g., as a collection of polynucleotide molecules), or in electronic form (e.g., as a collection of polynucleotide sequences stored in a computer-readable form, as in a computer system and/or as part of a computer program). The sequence information of the polynucleotides can be used in a variety of ways, e.g., as a resource for gene discovery, as a representation of sequences expressed in a selected cell type (e.g., cell type markers), and/or as markers of a given disease or disease state. For example, in the instant case, the sequences of polynucleotides and polypeptides corresponding to genes differentially expressed in cancer, as well as the nucleic acid and amino acid sequences of the genes themselves, can be provided in electronic form in a computer database.

In general, a disease marker is a representation of a gene product that is present in all cells affected by disease either at an increased or decreased level relative to a normal cell (e.g., a cell of the same or similar type that is not substantially affected by disease). For example, a polynucleotide sequence in a library can be a polynucleotide that represents an mRNA, polypeptide, or other gene product encoded by the polynucleotide, that is either overexpressed or underexpressed in a cancerous cell affected by cancer relative to a normal (i.e., substantially disease-free) cell.

The nucleotide sequence information of the library can be embodied in any suitable form, e.g., electronic or biochemical forms. For example, a library of sequence information embodied in electronic form comprises an accessible computer data file (or, in biochemical form, a collection of nucleic acid molecules) that contains the representative nucleotide sequences of genes that are differentially expressed (e.g., overexpressed or underexpressed) as between, for example, i) a cancerous cell and a normal cell; ii) a cancerous cell and a dysplastic cell; iii) a cancerous cell and a cell affected by a disease or condition other than cancer; iv) a metastatic cancerous cell and a normal cell and/or non-metastatic cancerous cell; v) a malignant cancerous cell and a non-malignant cancerous cell (or a normal cell) and/or vi) a dysplastic cell relative to a normal cell. Other combinations and comparisons of cells affected by various diseases or stages of disease will be readily apparent to the ordinarily skilled artisan. Biochemical embodiments of the library include a collection of nucleic acids that have the sequences of the genes in the library, where the nucleic acids can correspond to the entire gene in the library or to a fragment thereof, as described in greater detail below.

The polynucleotide libraries of the subject invention generally comprise sequence information of a plurality of polynucleotide sequences, where at least one of the polynucleotides has a sequence of any of sequence described herein. By plurality is meant at least 2, usually at least 3 and can include up to all of the sequences described herein. The length and number of polynucleotides in the library will vary with the nature of the library, e.g., if the library is an oligonucleotide array, a cDNA array, a computer database of the sequence information, etc.

Where the library is an electronic library, the nucleic acid sequence information can be present in a variety of media. “Media” refers to a manufacture, other than an isolated nucleic acid molecule, that contains the sequence information of the present invention. Such a manufacture provides the genome sequence or a subset thereof in a form that can be examined by means not directly applicable to the sequence as it exists in a nucleic acid. For example, the nucleotide sequence of the present invention, e.g. the nucleic acid sequences of any of the polynucleotides of the sequences described herein, can be recorded on computer readable media, e.g. any medium that can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as a floppy disc, a hard disc storage medium, and a magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.

One of skill in the art can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising a recording of the present sequence information. “Recorded” refers to a process for storing information on computer readable medium, using any such methods as known in the art. Any convenient data storage structure can be chosen, based on the means used to access the stored information. A variety of data processor programs and formats can be used for storage, e.g. word processing text file, database format, etc. In addition to the sequence information, electronic versions of libraries comprising one or more sequence described herein can be provided in conjunction or connection with other computer-readable information and/or other types of computer-readable files (e.g., searchable files, executable files, etc, including, but not limited to, for example, search program software, etc.).

By providing the nucleotide sequence in computer readable form, the information can be accessed for a variety of purposes. Computer software to access sequence information (e.g. the NCBI sequence database) is publicly available. For example, the gapped BLAST (Altschul et al., Nucleic Acids Res. (1997) 25:3389-3402) and BLAZE (Brutlag et al., Comp. Chem. (1993) 17:203) search algorithms on a Sybase system, or the TeraBLAST (TimeLogic, Crystal Bay, Nev.) program optionally running on a specialized computer platform available from TimeLogic, can be used to identify open reading frames (ORFs) within the genome that contain homology to ORFs from other organisms.

As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based system are suitable for use in the present invention. The data storage means can comprise any manufacture comprising a recording of the present sequence information as described above, or a memory access means that can access such a manufacture.

“Search means” refers to one or more programs implemented on the computer-based system, to compare a target sequence or target structural motif, or expression levels of a polynucleotide in a sample, with the stored sequence information. Search means can be used to identify fragments or regions of the genome that match a particular target sequence or target motif. A variety of known algorithms are publicly known and commercially available, e.g. MacPattern (EMBL), TeraBLAST (TimeLogic), BLASTN and BLASTX (NCBI). A “target sequence” can be any polynucleotide or amino acid sequence of six or more contiguous nucleotides or two or more amino acids, preferably from about 10 to 100 amino acids or from about 30 to 300 nt. A variety of means for comparing nucleic acids or polypeptides may be used to compare accomplish a sequence comparison (e.g., to analyze target sequences, target motifs, or relative expression levels) with the data storage means. A skilled artisan can readily recognize that any one of the publicly available homology search programs can be used to search the computer based systems of the present invention to compare of target sequences and motifs. Computer programs to analyze expression levels in a sample and in controls are also known in the art.

A “target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration that is formed upon the folding of the target motif, or on consensus sequences of regulatory or active sites. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences, kinase domains, receptor binding domains, SH2 domains, SH3 domains, phosphorylation sites, protein interaction domains, transmembrane domains, etc. Nucleic acid target motifs include, but are not limited to, hairpin structures, promoter sequences and other expression elements such as binding sites for transcription factors.

A variety of structural formats for the input and output means can be used to input and output the information in the computer-based systems of the present invention. One format for an output means ranks the relative expression levels of different polynucleotides. Such presentation provides a skilled artisan with a ranking of relative expression levels to determine a gene expression profile. A gene expression profile can be generated from, for example, a cDNA library prepared from mRNA isolated from a test cell suspected of being cancerous or pre-cancerous, comparing the sequences or partial sequences of the clones against the sequences in an electronic database, where the sequences of the electronic database represent genes differentially expressed in a cancerous cell, e.g., a cancerous breast cell. The number of clones having a sequence that has substantial similarity to a sequence that represents a gene differentially expressed in a cancerous cell is then determined, and the number of clones corresponding to each of such genes is determined. An increased number of clones that correspond to differentially expressed gene is present in the cDNA library of the test cell (relative to, for example, the number of clones expected in a cDNA of a normal cell) indicates that the test cell is cancerous.

As discussed above, the “library” as used herein also encompasses biochemical libraries of the polynucleotides of the sequences described herein, e.g., collections of nucleic acids representing the provided polynucleotides. The biochemical libraries can take a variety of forms, e.g., a solution of cDNAs, a pattern of probe nucleic acids stably associated with a surface of a solid support (i.e., an array) and the like. Of particular interest are nucleic acid arrays in which one or more of the genes described herein is represented by a sequence on the array. By array is meant an article of manufacture that has at least a substrate with at least two distinct nucleic acid targets on one of its surfaces, where the number of distinct nucleic acids can be considerably higher, typically being at least 10 nt, usually at least 20 nt and often at least 25 nt. A variety of different array formats have been developed and are known to those of skill in the art. The arrays of the subject invention find use in a variety of applications, including gene expression analysis, drug screening, mutation analysis and the like, as disclosed in the above-listed exemplary patent documents.

In addition to the above nucleic acid libraries, analogous libraries of polypeptides are also provided, where the polypeptides of the library will represent at least a portion of the polypeptides encoded by a gene corresponding to a sequence described herein.

Diagnostic and Other Methods Involving Detection of Differentially Expressed Genes

The present invention provides methods of using the polynucleotides described herein in, for example, diagnosis of cancer and classification of cancer cells according to expression profiles. In specific non-limiting embodiments, the methods are useful for detecting cancer cells, facilitating diagnosis of cancer and the severity of a cancer (e.g., tumor grade, tumor burden, and the like) in a subject, facilitating a determination of the prognosis of a subject, and assessing the responsiveness of the subject to therapy (e.g., by providing a measure of therapeutic effect through, for example, assessing tumor burden during or following a chemotherapeutic regimen). Detection can be based on detection of a polynucleotide that is differentially expressed in a cancer cell, and/or detection of a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell (“a polypeptide associated with cancer”). The detection methods of the invention can be conducted in vitro or in vivo, on isolated cells, or in whole tissues or a bodily fluid, e.g., blood, plasma, serum, urine, and the like).

In general, methods of the invention involving detection of a gene product (e.g., mRNA, cDNA generated from such mRNA, and polypeptides) involve contacting a sample with a probe specific for the gene product of interest. “Probe” as used herein in such methods is meant to refer to a molecule that specifically binds a gene product of interest (e.g., the probe binds to the target gene product with a specificity sufficient to distinguish binding to target over non-specific binding to non-target (background) molecules). “Probes” include, but are not necessarily limited to, nucleic acid probes (e.g., DNA, RNA, modified nucleic acid, and the like), antibodies (e.g., antibodies, antibody fragments that retain binding to a target epitope, single chain antibodies, and the like), or other polypeptide, peptide, or molecule (e.g., receptor ligand) that specifically binds a target gene product of interest.

The probe and sample suspected of having the gene product of interest are contacted under conditions suitable for binding of the probe to the gene product. For example, contacting is generally for a time sufficient to allow binding of the probe to the gene product (e.g. from several minutes to a few hours), and at a temperature and conditions of osmolarity and the like that provide for binding of the probe to the gene product at a level that is sufficiently distinguishable from background binding of the probe (e.g., under conditions that minimize non-specific binding). Suitable conditions for probe-target gene product binding can be readily determined using controls and other techniques available and known to one of ordinary skill in the art.

In this embodiment, the probe can be an antibody or other polypeptide, peptide, or molecule (e.g., receptor ligand) that specifically binds a target polypeptide of interest.

The detection methods can be provided as part of a kit. Thus, the invention further provides kits for detecting the presence and/or a level of a polynucleotide that is differentially expressed in a cancer cell (e.g., by detection of an mRNA encoded by the differentially expressed gene of interest), and/or a polypeptide encoded thereby, in a biological sample. Procedures using these kits can be performed by clinical laboratories, experimental laboratories, medical practitioners, or private individuals. The kits of the invention for detecting a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell comprise a moiety that specifically binds the polypeptide, which may be a specific antibody. The kits of the invention for detecting a polynucleotide that is differentially expressed in a cancer cell comprise a moiety that specifically hybridizes to such a polynucleotide. The kit may optionally provide additional components that are useful in the procedure, including, but not limited to, buffers, developing reagents, labels, reacting surfaces, means for detection, control samples, standards, instructions, and interpretive information.

Detecting a Polypeptide Encoded by a Polynucleotide that is Differentially Expressed in a Cancer Cell

In some embodiments, methods are provided for a detecting cancer cell by detecting in a cell, a polypeptide encoded by a gene differentially expressed in a cancer cell. Any of a variety of known methods can be used for detection, including, but not limited to, immunoassay, using an antibody specific for the encoded polypeptide, e.g., by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and the like; and functional assays for the encoded polypeptide, e.g., binding activity or enzymatic activity.

For example, an immunofluorescence assay can be easily performed on cells without first isolating the encoded polypeptide. The cells are first fixed onto a solid support, such as a microscope slide or microtiter well. This fixing step can permeabilize the cell membrane. The permeablization of the cell membrane permits the polypeptide-specific probe (e.g, antibody) to bind. Alternatively, where the polypeptide is secreted or membrane-bound, or is otherwise accessible at the cell-surface (e.g., receptors, and other molecule stably-associated with the outer cell membrane or otherwise stably associated with the cell membrane, such permeabilization may not be necessary.

Next, the fixed cells are exposed to an antibody specific for the encoded polypeptide. To increase the sensitivity of the assay, the fixed cells may be further exposed to a second antibody, which is labeled and binds to the first antibody, which is specific for the encoded polypeptide. Typically, the secondary antibody is detectably labeled, e.g., with a fluorescent marker. The cells which express the encoded polypeptide will be fluorescently labeled and easily visualized under the microscope. See, for example, Hashido et al. (1992) Biochem. Biophys. Res. Comm. 187:1241-1248.

As will be readily apparent to the ordinarily skilled artisan upon reading the present specification, the detection methods and other methods described herein can be varied. Such variations are within the intended scope of the invention. For example, in the above detection scheme, the probe for use in detection can be immobilized on a solid support, and the test sample contacted with the immobilized probe. Binding of the test sample to the probe can then be detected in a variety of ways, e.g., by detecting a detectable label bound to the test sample.

The present invention further provides methods for detecting the presence of and/or measuring a level of a polypeptide in a biological sample, which polypeptide is encoded by a polynucleotide that represents a gene differentially expressed in cancer, particularly in a polynucleotide that represents a gene differentially cancer cell, using a probe specific for the encoded polypeptide. In this embodiment, the probe can be a an antibody or other polypeptide, peptide, or molecule (e.g., receptor ligand) that specifically binds a target polypeptide of interest.

The methods generally comprise: a) contacting the sample with an antibody specific for a differentially expressed polypeptide in a test cell; and b) detecting binding between the antibody and molecules of the sample. The level of antibody binding (either qualitative or quantitative) indicates the cancerous state of the cell. For example, where the differentially expressed gene is increased in cancerous cells, detection of an increased level of antibody binding to the test sample relative to antibody binding level associated with a normal cell indicates that the test cell is cancerous.

Suitable controls include a sample known not to contain the encoded polypeptide; and a sample contacted with an antibody not specific for the encoded polypeptide, e.g., an anti-idiotype antibody. A variety of methods to detect specific antibody-antigen interactions are known in the art and can be used in the method, including, but not limited to, standard immunohistological methods, immunoprecipitation, an enzyme immunoassay, and a radioimmunoassay.

In general, the specific antibody will be detectably labeled, either directly or indirectly. Direct labels include radioisotopes; enzymes whose products are detectable (e.g., luciferase, β-galactosidase, and the like); fluorescent labels (e.g., fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g., ¹⁵²Eu, or others of the lanthanide series, attached to the antibody through metal chelating groups such as EDTA; chemiluminescent compounds, e.g., luminol, isoluminol, acridinium salts, and the like; bioluminescent compounds, e.g., luciferin, aequorin (green fluorescent protein), and the like.

The antibody may be attached (coupled) to an insoluble support, such as a polystyrene plate or a bead. Indirect labels include second antibodies specific for antibodies specific for the encoded polypeptide (“first specific antibody”), wherein the second antibody is labeled as described above; and members of specific binding pairs, e.g., biotin-avidin, and the like. The biological sample may be brought into contact with and immobilized on a solid support or carrier, such as nitrocellulose, that is capable of immobilizing cells, cell particles, or soluble proteins. The support may then be washed with suitable buffers, followed by contacting with a detectably-labeled first specific antibody. Detection methods are known in the art and will be chosen as appropriate to the signal emitted by the detectable label. Detection is generally accomplished in comparison to suitable controls, and to appropriate standards.

In some embodiments, the methods are adapted for use in vivo, e.g., to locate or identify sites where cancer cells are present. In these embodiments, a detectably-labeled moiety, e.g., an antibody, which is specific for a cancer-associated polypeptide is administered to an individual (e.g., by injection), and labeled cells are located using standard imaging techniques, including, but not limited to, magnetic resonance imaging, computed tomography scanning, and the like. In this manner, cancer cells are differentially labeled.

Detecting a Polynucleotide that Represents a Gene Differentially Expressed in a Cancer Cell

In some embodiments, methods are provided for detecting a cancer cell by detecting expression in the cell of a transcript or that is differentially expressed in a cancer cell. Any of a variety of known methods can be used for detection, including, but not limited to, detection of a transcript by hybridization with a polynucleotide that hybridizes to a polynucleotide that is differentially expressed in a cancer cell; detection of a transcript by a polymerase chain reaction using specific oligonucleotide primers; in situ hybridization of a cell using as a probe a polynucleotide that hybridizes to a gene that is differentially expressed in a cancer cell and the like.

In many embodiments, the levels of a subject gene product are measured. By measured is meant qualitatively or quantitatively estimating the level of the gene product in a first biological sample either directly (e.g. by determining or estimating absolute levels of gene product) or relatively by comparing the levels to a second control biological sample. In many embodiments the second control biological sample is obtained from an individual not having not having cancer. As will be appreciated in the art, once a standard control level of gene expression is known, it can be used repeatedly as a standard for comparison. Other control samples include samples of cancerous tissue.

The methods can be used to detect and/or measure mRNA levels of a gene that is differentially expressed in a cancer cell. In some embodiments, the methods comprise: a) contacting a sample with a polynucleotide that corresponds to a differentially expressed gene described herein under conditions that allow hybridization; and b) detecting hybridization, if any. Detection of differential hybridization, when compared to a suitable control, is an indication of the presence in the sample of a polynucleotide that is differentially expressed in a cancer cell. Appropriate controls include, for example, a sample that is known not to contain a polynucleotide that is differentially expressed in a cancer cell. Conditions that allow hybridization are known in the art, and have been described in more detail above.

Detection can also be accomplished by any known method, including, but not limited to, in situ hybridization, PCR (polymerase chain reaction), RT-PCR (reverse transcription-PCR), and “Northern” or RNA blotting, arrays, microarrays, etc, or combinations of such techniques, using a suitably labeled polynucleotide. A variety of labels and labeling methods for polynucleotides are known in the art and can be used in the assay methods of the invention. Specific hybridization can be determined by comparison to appropriate controls.

Polynucleotides described herein are used for a variety of purposes, such as probes for detection of and/or measurement of, transcription levels of a polynucleotide that is differentially expressed in a cancer cell. Additional disclosure about preferred regions of the disclosed polynucleotide sequences is found in the Examples. A probe that hybridizes specifically to a polynucleotide disclosed herein should provide a detection signal at least 2-, 5-, 10-, or 20-fold higher than the background hybridization provided with other unrelated sequences. It should be noted that “probe” as used in this context of detection of nucleic acid is meant to refer to a polynucleotide sequence used to detect a differentially expressed gene product in a test sample. As will be readily appreciated by the ordinarily skilled artisan, the probe can be detectably labeled and contacted with, for example, an array comprising immobilized polynucleotides obtained from a test sample (e.g., mRNA). Alternatively, the probe can be immobilized on an array and the test sample detectably labeled. These and other variations of the methods of the invention are well within the skill in the art and are within the scope of the invention.

Labeled nucleic acid probes may be used to detect expression of a gene corresponding to the provided polynucleotide. In Northern blots, mRNA is separated electrophoretically and contacted with a probe. A probe is detected as hybridizing to an mRNA species of a particular size. The amount of hybridization can be quantitated to determine relative amounts of expression, for example under a particular condition. Probes are used for in situ hybridization to cells to detect expression. Probes can also be used in vivo for diagnostic detection of hybridizing sequences. Probes are typically labeled with a radioactive isotope. Other types of detectable labels can be used such as chromophores, fluorophores, and enzymes. Other examples of nucleotide hybridization assays are described in WO92/02526 and U.S. Pat. No. 5,124,246.

PCR is another means for detecting small amounts of target nucleic acids, methods for which may be found in Sambrook, et al. Molecular Cloning: A Laboratory Manual, CSH Press 1989, pp. 14.2-14.33.

A detectable label may be included in the amplification reaction. Suitable detectable labels include fluorochromes, (e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2′,7′-dimethoxy-4′,5′-dichloro-6-carboxyfluorescein, 6-carboxy-X-rhodamine (ROX), 6-carboxy-2′,4′,7′,4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) or N,N,N′,N′-tetramethyl-6-carboxyrhodamine (TAMRA)), radioactive labels, (e.g. ³²P, ³⁵S, ³H, etc.), and the like. The label may be a two stage system, where the polynucleotides is conjugated to biotin, haptens, etc. having a high affinity binding partner, e.g. avidin, specific antibodies, etc., where the binding partner is conjugated to a detectable label. The label may be conjugated to one or both of the primers. Alternatively, the pool of nucleotides used in the amplification is labeled, so as to incorporate the label into the amplification product.

Arrays

Polynucleotide arrays provide a high throughput technique that can assay a large number of polynucleotides or polypeptides in a sample. This technology can be used as a tool to test for differential expression.

A variety of methods of producing arrays, as well as variations of these methods, are known in the art and contemplated for use in the invention. For example, arrays can be created by spotting polynucleotide probes onto a substrate (e.g., glass, nitrocellulose, etc.) in a two-dimensional matrix or array having bound probes. The probes can be bound to the substrate by either covalent bonds or by non-specific interactions, such as hydrophobic interactions.

Samples of polynucleotides can be detectably labeled (e.g., using radioactive or fluorescent labels) and then hybridized to the probes. Double stranded polynucleotides, comprising the labeled sample polynucleotides bound to probe polynucleotides, can be detected once the unbound portion of the sample is washed away. Alternatively, the polynucleotides of the test sample can be immobilized on the array, and the probes detectably labeled. Techniques for constructing arrays and methods of using these arrays are described in, for example, Schena et al. (1996) Proc Natl Acad Sci USA. 93(20):10614-9; Schena et al. (1995) Science 270(5235):467-70; Shalon et al. (1996) Genome Res. 6(7):639-45, U.S. Pat. No. 5,807,522, EP 799 897; WO 97/29212; WO 97/27317; EP 785 280; WO 97/02357; U.S. Pat. No. 5,593,839; U.S. Pat. No. 5,578,832; EP 728 520; U.S. Pat. No. 5,599,695; EP 721 016; U.S. Pat. No. 5,556,752; WO 95/22058; and U.S. Pat. No. 5,631,734. In most embodiments, the “probe” is detectably labeled. In other embodiments, the probe is immobilized on the array and not detectably labeled.

Arrays can be used, for example, to examine differential expression of genes and can be used to determine gene function. For example, arrays can be used to detect differential expression of a gene corresponding to a polynucleotide described herein, where expression is compared between a test cell and control cell (e.g., cancer cells and normal cells). For example, high expression of a particular message in a cancer cell, which is not observed in a corresponding normal cell, can indicate a cancer specific gene product. Exemplary uses of arrays are further described in, for example, Pappalarado et al., Sem. Radiation Oncol. (1998) 8:217; and Ramsay, Nature Biotechnol. (1998) 16:40. Furthermore, many variations on methods of detection using arrays are well within the skill in the art and within the scope of the present invention. For example, rather than immobilizing the probe to a solid support, the test sample can be immobilized on a solid support which is then contacted with the probe.

Diagnosis, Prognosis, Assessment of Therapy (Therametrics), and Management of Cancer

The polynucleotides described herein, as well as their gene products and corresponding genes and gene products, are of particular interest as genetic or biochemical markers (e.g., in blood or tissues) that will detect the earliest changes along the carcinogenesis pathway and/or to monitor the efficacy of various therapies and preventive interventions.

For example, the level of expression of certain polynucleotides can be indicative of a poorer prognosis, and therefore warrant more aggressive chemo- or radio-therapy for a patient or vice versa. The correlation of novel surrogate tumor specific features with response to treatment and outcome in patients can define prognostic indicators that allow the design of tailored therapy based on the molecular profile of the tumor. These therapies include antibody targeting, antagonists (e.g., small molecules), and gene therapy.

Determining expression of certain polynucleotides and comparison of a patient's profile with known expression in normal tissue and variants of the disease allows a determination of the best possible treatment for a patient, both in terms of specificity of treatment and in terms of comfort level of the patient. Surrogate tumor markers, such as polynucleotide expression, can also be used to better classify, and thus diagnose and treat, different forms and disease states of cancer. Two classifications widely used in oncology that can benefit from identification of the expression levels of the genes corresponding to the polynucleotides described herein are staging of the cancerous disorder, and grading the nature of the cancerous tissue.

The polynucleotides that correspond to differentially expressed genes, as well as their encoded-gene products, can be useful to monitor patients having or susceptible to cancer to detect potentially malignant events at a molecular level before they are detectable at a gross morphological level. In addition, the polynucleotides described herein, as well as the genes corresponding to such polynucleotides, can be useful as therametrics, e.g., to assess the effectiveness of therapy by using the polynucleotides or their encoded gene products, to assess, for example, tumor burden in the patient before, during, and after therapy.

Furthermore, a polynucleotide identified as corresponding to a gene that is differentially expressed in, and thus is important for, one type of cancer can also have implications for development or risk of development of other types of cancer, e.g., where a polynucleotide represents a gene differentially expressed across various cancer types. Thus, for example, expression of a polynucleotide corresponding to a gene that has clinical implications for cancer can also have clinical implications for metastatic breast cancer, colon cancer, or ovarian cancer, etc.

Staging. Staging is a process used by physicians to describe how advanced the cancerous state is in a patient. Staging assists the physician in determining a prognosis, planning treatment and evaluating the results of such treatment. Staging systems vary with the types of cancer, but generally involve the following “TNM” system: the type of tumor, indicated by T; whether the cancer has metastasized to nearby lymph nodes, indicated by N; and whether the cancer has metastasized to more distant parts of the body, indicated by M. Generally, if a cancer is only detectable in the area of the primary lesion without having spread to any lymph nodes it is called Stage I. If it has spread only to the closest lymph nodes, it is called Stage II. In Stage III, the cancer has generally spread to the lymph nodes in near proximity to the site of the primary lesion. Cancers that have spread to a distant part of the body, such as the liver, bone, brain or other site, are Stage IV, the most advanced stage.

The polynucleotides and corresponding genes and gene products described herein can facilitate fine-tuning of the staging process by identifying markers for the aggressiveness of a cancer, e.g. the metastatic potential, as well as the presence in different areas of the body. Thus, a Stage II cancer with a polynucleotide signifying a high metastatic potential cancer can be used to change a borderline Stage II tumor to a Stage III tumor, justifying more aggressive therapy. Conversely, the presence of a polynucleotide signifying a lower metastatic potential allows more conservative staging of a tumor.

One type of breast cancer is ductal carcinoma in situ (DCIS): DCIS is when the breast cancer cells are completely contained within the breast ducts (the channels in the breast that carry milk to the nipple), and have not spread into the surrounding breast tissue. This may also be referred to as non-invasive or intraductal cancer, as the cancer cells have not yet spread into the surrounding breast tissue and so usually have not spread into any other part of the body.

Lobular carcinoma in situ breast cancer (LCIS) means that cell changes are found in the lining of the lobules of the breast. It can be present in both breasts. It is also referred to as non-invasive cancer as it has not spread into the surrounding breast tissue.

Invasive breast cancer can be staged as follows: Stage 1 tumours: these measure less than two centimeters. The lymph glands in the armpit are not affected and there are no signs that the cancer has spread elsewhere in the body; Stage 2 tumours: these measure between two and five centimeters, or the lymph glands in the armpit are affected, or both. However, there are no signs that the cancer has spread further; Stage 3 tumours: these are larger than five centimeters and may be attached to surrounding structures such as the muscle or skin. The lymph glands are usually affected, but there are no signs that the cancer has spread beyond the breast or the lymph glands in the armpit; Stage 4 tumours: these are of any size, but the lymph glands are usually affected and the cancer has spread to other parts of the body. This is secondary breast cancer.

Grading of cancers. Grade is a term used to describe how closely a tumor resembles normal tissue of its same type. The microscopic appearance of a tumor is used to identify tumor grade based on parameters such as cell morphology, cellular organization, and other markers of differentiation. As a general rule, the grade of a tumor corresponds to its rate of growth or aggressiveness, with undifferentiated or high-grade tumors generally being more aggressive than well-differentiated or low-grade tumors.

The polynucleotides of the Sequence Listing, and their corresponding genes and gene products, can be especially valuable in determining the grade of the tumor, as they not only can aid in determining the differentiation status of the cells of a tumor, they can also identify factors other than differentiation that are valuable in determining the aggressiveness of a tumor, such as metastatic potential.

Low grade means that the cancer cells look very like the normal cells. They are usually slowly growing and are less likely to spread. In high grade tumors the cells look very abnormal. They are likely to grow more quickly and are more likely to spread.

Assessment of proliferation of cells in tumor. The differential expression level of the polynucleotides described herein can facilitate assessment of the rate of proliferation of tumor cells, and thus provide an indicator of the aggressiveness of the rate of tumor growth. For example, assessment of the relative expression levels of genes involved in cell cycle can provide an indication of cellular proliferation, and thus serve as a marker of proliferation.

Detection of Cancer.

The polynucleotides corresponding to genes that exhibit the appropriate expression pattern can be used to detect cancer in a subject. The expression of appropriate polynucleotides can be used in the diagnosis, prognosis and management of cancer. Detection of cancer can be determined using expression levels of any of these sequences alone or in combination with the levels of expression of other known cancer genes. Determination of the aggressive nature and/or the metastatic potential of a cancer can be determined by comparing levels of one or more gene products of the genes corresponding to the polynucleotides described herein, and comparing total levels of another sequence known to vary in cancerous tissue, e.g., expression of p53, DCC, ras, FAP (see, e.g., Fearon E R, et al., Cell (1990) 61(5):759; Hamilton S R et al., Cancer (1993) 72:957; Bodmer W, et al., Nat Genet. (1994) 4(3):217; Fearon E R, Ann NY Acad. Sci. (1995) 768:101). For example, development of cancer can be detected by examining the level of expression of a gene corresponding to a polynucleotides described herein to the levels of oncogenes (e.g. ras) or tumor suppressor genes (e.g. FAP or p53). Thus expression of specific marker polynucleotides can be used to discriminate between normal and cancerous tissue, to discriminate between cancers with different cells of origin, to discriminate between cancers with different potential metastatic rates, etc. For a review of other markers of cancer, see, e.g., Hanahan et al. (2000) Cell 100:57-70.

Treatment of Cancer

The invention further provides methods for reducing growth of cancer cells. The methods provide for decreasing the expression of a gene that is differentially expressed in a cancer cell or decreasing the level of and/or decreasing an activity of a cancer-associated polypeptide. In general, the methods comprise contacting a cancer cell with a substance that modulates (1) expression of a gene that is differentially expressed in cancer; or (2) a level of and/or an activity of a cancer-associated polypeptide.

“Reducing growth of cancer cells” includes, but is not limited to, reducing proliferation of cancer cells, and reducing the incidence of a non-cancerous cell becoming a cancerous cell. Whether a reduction in cancer cell growth has been achieved can be readily determined using any known assay, including, but not limited to, [³H]-thymidine incorporation; counting cell number over a period of time; detecting and/or measuring a marker associated with breast cancer (e.g., PSA).

The present invention provides methods for treating cancer, generally comprising administering to an individual in need thereof a substance that reduces cancer cell growth, in an amount sufficient to reduce cancer cell growth and treat the cancer. Whether a substance, or a specific amount of the substance, is effective in treating cancer can be assessed using any of a variety of known diagnostic assays for cancer, including, but not limited to, proctoscopy, rectal examination, biopsy, contrast radiographic studies, CAT scan, and detection of a tumor marker associated with cancer in the blood of the individual (e.g., PSA (breast-specific antigen)). The substance can be administered systemically or locally. Thus, in some embodiments, the substance is administered locally, and cancer growth is decreased at the site of administration. Local administration may be useful in treating, e.g., a solid tumor.

A substance that reduces cancer cell growth can be targeted to a cancer cell. Thus, in some embodiments, the invention provides a method of delivering a drug to a cancer cell, comprising administering a drug-antibody complex to a subject, wherein the antibody is specific for a cancer-associated polypeptide, and the drug is one that reduces cancer cell growth, a variety of which are known in the art. Targeting can be accomplished by coupling (e.g., linking, directly or via a linker molecule, either covalently or non-covalently, so as to form a drug-antibody complex) a drug to an antibody specific for a cancer-associated polypeptide. Methods of coupling a drug to an antibody are well known in the art and need not be elaborated upon herein.

Tumor Classification and Patient Stratification

The invention further provides for methods of classifying tumors, and thus grouping or “stratifying” patients, according to the expression profile of selected differentially expressed genes in a tumor. Differentially expressed genes can be analyzed for correlation with other differentially expressed genes in a single tumor type or across tumor types. Genes that demonstrate consistent correlation in expression profile in a given cancer cell type (e.g., in a cancer cell or type of cancer) can be grouped together, e.g., when one gene is overexpressed in a tumor, a second gene is also usually overexpressed. Tumors can then be classified according to the expression profile of one or more genes selected from one or more groups.

The tumor of each patient in a pool of potential patients can be classified as described above. Patients having similarly classified tumors can then be selected for participation in an investigative or clinical trial of a cancer therapeutic where a homogeneous population is desired. The tumor classification of a patient can also be used in assessing the efficacy of a cancer therapeutic in a heterogeneous patient population. In addition, therapy for a patient having a tumor of a given expression profile can then be selected accordingly.

In another embodiment, differentially expressed gene products (e.g., polypeptides or polynucleotides encoding such polypeptides) may be effectively used in treatment through vaccination. The growth of cancer cells is naturally limited in part due to immune surveillance. Stimulation of the immune system using a particular tumor-specific antigen enhances the effect towards the tumor expressing the antigen. An active vaccine comprising a polypeptide encoded by the cDNA of this invention would be appropriately administered to subjects having an alteration, e.g., overabundance, of the corresponding RNA, or those predisposed for developing cancer cells with an alteration of the same RNA. Polypeptide antigens are typically combined with an adjuvant as part of a vaccine composition. The vaccine is preferably administered first as a priming dose, and then again as a boosting dose, usually at least four weeks later. Further boosting doses may be given to enhance the effect. The dose and its timing are usually determined by the person responsible for the treatment.

The invention also encompasses the selection of a therapeutic regimen based upon the expression profile of differentially expressed genes in the patient's tumor. For example, a tumor can be analyzed for its expression profile of the genes corresponding to SEQ ID NOS:1-23767 as described herein, e.g., the tumor is analyzed to determine which genes are expressed at elevated levels or at decreased levels relative to normal cells of the same tissue type. The expression patterns of the tumor are then compared to the expression patterns of tumors that respond to a selected therapy. Where the expression profiles of the test tumor cell and the expression profile of a tumor cell of known drug responsivity at least substantially match (e.g., selected sets of genes at elevated levels in the tumor of known drug responsivity and are also at elevated levels in the test tumor cell), then the therapeutic agent selected for therapy is the drug to which tumors with that expression pattern respond.

Pattern Matching in Diagnosis Using Arrays

In another embodiment, the diagnostic and/or prognostic methods of the invention involve detection of expression of a selected set of genes in a test sample to produce a test expression pattern (TEP). The TEP is compared to a reference expression pattern (REP), which is generated by detection of expression of the selected set of genes in a reference sample (e.g., a positive or negative control sample). The selected set of genes includes at least one of the genes of the invention, which genes correspond to the polynucleotide sequences described herein. Of particular interest is a selected set of genes that includes gene differentially expressed in the disease for which the test sample is to be screened.

Identification of Therapeutic Targets and Anti-Cancer Therapeutic Agents

The present invention also encompasses methods for identification of agents having the ability to modulate activity of a differentially expressed gene product, as well as methods for identifying a differentially expressed gene product as a therapeutic target for treatment of cancer.

Identification of compounds that modulate activity of a differentially expressed gene product can be accomplished using any of a variety of drug screening techniques. Such agents are candidates for development of cancer therapies. Of particular interest are screening assays for agents that have tolerable toxicity for normal, non-cancerous human cells. The screening assays of the invention are generally based upon the ability of the agent to modulate an activity of a differentially expressed gene product and/or to inhibit or suppress phenomenon associated with cancer (e.g., cell proliferation, colony formation, cell cycle arrest, metastasis, and the like).

Screening of Candidate Agents

Screening assays can be based upon any of a variety of techniques readily available and known to one of ordinary skill in the art. In general, the screening assays involve contacting a cancerous cell with a candidate agent, and assessing the effect upon biological activity of a differentially expressed gene product. The effect upon a biological activity can be detected by, for example, detection of expression of a gene product of a differentially expressed gene (e.g., a decrease in mRNA or polypeptide levels, would in turn cause a decrease in biological activity of the gene product). Alternatively or in addition, the effect of the candidate agent can be assessed by examining the effect of the candidate agent in a functional assay. For example, where the differentially expressed gene product is an enzyme, then the effect upon biological activity can be assessed by detecting a level of enzymatic activity associated with the differentially expressed gene product. The functional assay will be selected according to the differentially expressed gene product. In general, where the differentially expressed gene is increased in expression in a cancerous cell, agents of interest are those that decrease activity of the differentially expressed gene product.

Assays described infra can be readily adapted in the screening assay embodiments of the invention. Exemplary assays useful in screening candidate agents include, but are not limited to, hybridization-based assays (e.g., use of nucleic acid probes or primers to assess expression levels), antibody-based assays (e.g., to assess levels of polypeptide gene products), binding assays, (e.g., to detect interaction of a candidate agent with a differentially expressed polypeptide, which assays may be competitive assays where a natural or synthetic ligand for the polypeptide is available), and the like; Additional exemplary assays include, but are not necessarily limited to, cell proliferation assays, antisense knockout assays, assays to detect inhibition of cell cycle, assays of induction of cell death/apoptosis, and the like. Generally such assays are conducted in vitro, but many assays can be adapted for in vivo analyses, e.g., in an animal model of the cancer.

Identification of Therapeutic Targets

In another embodiment, the invention contemplates identification of differentially expressed genes and gene products as therapeutic targets. In some respects, this is the converse of the assays described above for identification of agents having activity in modulating (e.g., decreasing or increasing) activity of a differentially expressed gene product.

In this embodiment, therapeutic targets are identified by examining the effect(s) of an agent that can be demonstrated or has been-demonstrated to modulate a cancerous phenotype (e.g., inhibit or suppress or prevent development of a cancerous phenotype). Such agents are generally referred to herein as an “anti-cancer agent”, which agents encompass chemotherapeutic agents. For example, the agent can be an antisense oligonucleotide that is specific for a selected gene transcript. For example, the antisense oligonucleotide may have a sequence corresponding to a sequence of a differentially expressed gene described herein, e.g., a sequence of one of SEQ ID NOS:1-23767.

Assays for identification of therapeutic targets can be conducted in a variety of ways using methods that are well known to one of ordinary skill in the art. For example, a test cancerous cell that expresses or overexpresses a differentially expressed gene is contacted with an anti-cancer agent, the effect upon a cancerous phenotype and a biological activity of the candidate gene product assessed. The biological activity of the candidate gene product can be assayed be examining, for example, modulation of expression of a gene encoding the candidate gene product (e.g., as detected by, for example, an increase or decrease in transcript levels or polypeptide levels), or modulation of an enzymatic or other activity of the gene product. The cancerous phenotype can be, for example, cellular proliferation, loss of contact inhibition of growth (e.g., colony formation), tumor growth (in vitro or in vivo), and the like. Alternatively or in addition, the effect of modulation of a biological activity of the candidate target gene upon cell death/apoptosis or cell cycle regulation can be assessed.

Inhibition or suppression of a cancerous phenotype, or an increase in cell death or apoptosis as a result of modulation of biological activity of a candidate gene product indicates that the candidate gene product is a suitable target for cancer therapy. Assays described infra can be readily adapted for assays for identification of therapeutic targets. Generally such assays are conducted in vitro, but many assays can be adapted for in vivo analyses, e.g., in an appropriate, art-accepted animal model of the cancer.

Candidate Agents

The term “agent” as used herein describes any molecule, e.g. protein or pharmaceutical, with the capability of modulating a biological activity of a gene product of a differentially expressed gene. Generally a plurality of assay mixtures are run in parallel with different agent concentrations to obtain a differential response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection.

Candidate agents encompass numerous chemical classes, though typically they are organic molecules, preferably small organic compounds having a molecular weight of more than 50 and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including, but not limited to: peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof.

Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts (including extracts from human tissue to identify endogenous factors affecting differentially expressed gene products) are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs.

Exemplary candidate agents of particular interest include, but are not limited to, antisense and RNAi polynucleotides, and antibodies, soluble receptors, and the like. Antibodies and soluble receptors are of particular interest as candidate agents where the target differentially expressed gene product is secreted or accessible at the cell-surface (e.g., receptors and other molecule stably-associated with the outer cell membrane).

For method that involve RNAi (RNA interference), a double stranded RNA (dsRNA) molecule is usually used. The dsRNA is prepared to be substantially identical to at least a segment of a subject polynucleotide (e.g. a cDNA or gene). In general, the dsRNA is selected to have at least 70%, 75%, 80%, 85% or 90% sequence identity with the subject polynucleotide over at least a segment of the candidate gene. In other instances, the sequence identity is even higher, such as 95%, 97% or 99%, and in still other instances, there is 100% sequence identity with the subject polynucleotide over at least a segment of the subject polynucleotide. The size of the segment over which there is sequence identity can vary depending upon the size of the subject polynucleotide. In general, however, there is substantial sequence identity over at least 15, 20, 25, 30, 35, 40 or 50 nucleotides. In other instances, there is substantial sequence identity over at least 100, 200, 300, 400, 500 or 1000 nucleotides; in still other instances, there is substantial sequence identity over the entire length of the subject polynucleotide, i.e., the coding and non-coding region of the candidate gene.

Because only substantial sequence similarity between the subject polynucleotide and the dsRNA is necessary, sequence variations between these two species arising from genetic mutations, evolutionary divergence and polymorphisms can be tolerated. Moreover, as described further infra, the dsRNA can include various modified or nucleotide analogs.

Usually the dsRNA consists of two separate complementary RNA strands. However, in some instances, the dsRNA may be formed by a single strand of RNA that is self-complementary, such that the strand loops back upon itself to form a hairpin loop. Regardless of form, RNA duplex formation can occur inside or outside of a cell.

The size of the dsRNA that is utilized varies according to the size of the subject polynucleotide whose expression is to be suppressed and is sufficiently long to be effective in reducing expression of the subject polynucleotide in a cell. Generally, the dsRNA is at least 10-15 nucleotides long. In certain applications, the dsRNA is less than 20, 21, 22, 23, 24 or 25 nucleotides in length. In other instances, the dsRNA is at least 50, 100, 150 or 200 nucleotides in length. The dsRNA can be longer still in certain other applications, such as at least 300, 400, 500 or 600 nucleotides. Typically, the dsRNA is not longer than 3000 nucleotides. The optimal size for any particular subject polynucleotide can be determined by one of ordinary skill in the art without undue experimentation by varying the size of the dsRNA in a systematic fashion and determining whether the size selected is effective in interfering with expression of the subject polynucleotide.

dsRNA can be prepared according to any of a number of methods that are known in the art, including in vitro and in vivo methods, as well as by synthetic chemistry approaches.

In vitro methods. Certain methods generally involve inserting the segment corresponding to the candidate gene that is to be transcribed between a promoter or pair of promoters that are oriented to drive transcription of the inserted segment and then utilizing an appropriate RNA polymerase to carry out transcription. One such arrangement involves positioning a DNA fragment corresponding to the candidate gene or segment thereof into a vector such that it is flanked by two opposable polymerase-specific promoters that can be same or different. Transcription from such promoters produces two complementary RNA strands that can subsequently anneal to form the desired dsRNA. Exemplary plasmids for use in such systems include the plasmid (PCR 4.0 TOPO) (available from Invitrogen). Another example is the vector pGEM-T (Promega, Madison, Wis.) in which the oppositely oriented promoters are T7 and SP6; the T3 promoter can also be utilized.

In a second arrangement, DNA fragments corresponding to the segment of the subject polynucleotide that is to be transcribed is inserted both in the sense and antisense orientation downstream of a single promoter. In this system, the sense and antisense fragments are cotranscribed to generate a single RNA strand that is self-complementary and thus can form dsRNA.

Various other in vitro methods have been described. Examples of such methods include, but are not limited to, the methods described by Sadher et al. (Biochem. Int. 1-4:1015, 1987); by Bhattacharyya (Nature 343:484, 1990); and by Livache, et al. (U.S. Pat. No. 5,795,715), each of which is incorporated herein by reference in its entirety.

Single-stranded RNA can also be produced using a combination of enzymatic and organic synthesis or by total organic synthesis. The use of synthetic chemical methods enable one to introduce desired modified nucleotides or nucleotide analogs into the dsRNA.

In vivo methods. dsRNA can also be prepared in vivo according to a number of established methods (see, e.g., Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual, 2^(nd) ed.; Transcription and Translation (B. D. Hames, and S. J. Higgins, Eds., 1984); DNA Cloning, volumes I and II (D. N. Glover, Ed., 1985); and Oligonucleotide Synthesis (M. J. Gait, Ed., 1984, each of which is incorporated herein by reference in its entirety).

Once the single-stranded RNA has been formed, the complementary strands are allowed to anneal to form duplex RNA. Transcripts are typically treated with DNAase and further purified according to established protocols to remove proteins. Usually such purification methods are not conducted with phenol:chloroform. The resulting purified transcripts are subsequently dissolved in RNAase free water or a buffer of suitable composition.

dsRNA is generated by annealing the sense and anti-sense RNA in vitro. Generally, the strands are initially denatured to keep the strands separate and to avoid self-annealing. During the annealing process, typically certain ratios of the sense and antisense strands are combined to facilitate the annealing process. In some instances, a molar ratio of sense to antisense strands of 3:7 is used; in other instances, a ratio of 4:6 is utilized; and in still other instances, the ratio is 1:1.

The buffer composition utilized during the annealing process can in some instances affect the efficacy of the annealing process and subsequent transfection procedure. While some have indicated that the buffered solution used to carry out the annealing process should include a potassium salt such as potassium chloride (e.g. at a concentration of about 80 mM). In some embodiments, the buffer is substantially postassium free. Once single-stranded RNA has annealed to form duplex RNA, typically any single-strand overhangs are removed using an enzyme that specifically cleaves such overhangs (e.g., RNAase A or RNAase T).

Once the dsRNA has been formed, it is introduced into a reference cell, which can include an individual cell or a population of cells (e.g., a tissue, an embryo and an entire organism). The cell can be from essentially any source, including animal, plant, viral, bacterial, fungal and other sources. If a tissue, the tissue can include dividing or nondividing and differentiated or undifferentiated cells. Further, the tissue can include germ line cells and somatic cells. Examples of differentiated cells that can be utilized include, but are not limited to, neurons, glial cells, blood cells, megakaryocytes, lymphocytes, macrophages, neutrophils, eosinophils, basophils, mast cells, leukocytes, granulocytes, keratinocytes, adipocytes, osteoblasts, osteoclasts, hepatocytes, cells of the endocrine or exocrine glands, fibroblasts, myocytes, cardiomyocytes, and endothelial cells. The cell can be an individual cell of an embryo, and can be a blastocyte or an oocyte.

Certain methods are conducted using model systems for particular cellular states (e.g., a disease). For instance, certain methods provided herein are conducted with a cancer cell lines that serves as a model system for investigating genes that are correlated with various cancers.

A number of options can be utilized to deliver the dsRNA into a cell or population of cells such as in a cell culture, tissue or embryo. For instance, RNA can be directly introduced intracellularly. Various physical methods are generally utilized in such instances, such as administration by microinjection (see, e.g., Zernicka-Goetz, et al. (1997) Development 124:1133-1137; and Wianny, et al. (1998) Chromosoma 107: 430-439).

Other options for cellular delivery include permeabilizing the cell membrane and electroporation in the presence of the dsRNA, liposome-mediated transfection, or transfection using chemicals such as calcium phosphate. A number of established gene therapy techniques can also be utilized to introduce the dsRNA into a cell. By introducing a viral construct within a viral particle, for instance, one can achieve efficient introduction of an expression construct into the cell and transcription of the RNA encoded by the construct.

If the dsRNA is to be introduced into an organism or tissue, gene gun technology is an option that can be employed. This generally involves immobilizing the dsRNA on a gold particle which is subsequently fired into the desired tissue. Research has also shown that mammalian cells have transport mechanisms for taking in dsRNA (see, e.g., Asher, et al. (1969) Nature 223:715-717). Consequently, another delivery option is to administer the dsRNA extracellularly into a body cavity, interstitial space or into the blood system of the mammal for subsequent uptake by such transport processes. The blood and lymph systems and the cerebrospinal fluid are potential sites for injecting dsRNA. Oral, topical, parenteral, rectal and intraperitoneal administration are also possible modes of administration.

The composition introduced can also include various other agents in addition to the dsRNA. Examples of such agents include, but are not limited to, those that stabilize the dsRNA, enhance cellular uptake and/or increase the extent of interference. Typically, the dsRNA is introduced in a buffer that is compatible with the composition of the cell into which the RNA is introduced to prevent the cell from being shocked. The minimum size of the dsRNA that effectively achieves gene silencing can also influence the choice of delivery system and solution composition.

Sufficient dsRNA is introduced into the tissue to cause a detectable change in expression of a taget gene (assuming the candidate gene is in fact being expressed in the cell into which the dsRNA is introduced) using available detection methodologies. Thus, in some instances, sufficient dsRNA is introduced to achieve at least a 5-10% reduction in candidate gene expression as compared to a cell in which the dsRNA is not introduced. In other instances, inhibition is at least 20, 30, 40, or 50%. In still other instances, the inhibition is at least 60, 70, 80, 90 or 95%. Expression in some instances is essentially completely inhibited to undetectable levels.

The amount of dsRNA introduced depends upon various factors such as the mode of administration utilized, the size of the dsRNA, the number of cells into which dsRNA is administered, and the age and size of an animal if dsRNA is introduced into an animal. An appropriate amount can be determined by those of ordinary skill in the art by initially administering dsRNA at several different concentrations for example, for example. In certain instances when dsRNA is introduced into a cell culture, the amount of dsRNA introduced into the cells varies from about 0.5 to 3 μg per 10⁶ cells.

A number of options are available to detect interference of candidate gene expression (i.e., to detect candidate gene silencing). In general, inhibition in expression is detected by detecting a decrease in the level of the protein encoded by the candidate gene, determining the level of mRNA transcribed from the gene and/or detecting a change in phenotype associated with candidate gene expression.

Use of Polypeptides to Screen for Peptide Analogs and Antagonists

Polypeptides encoded by differentially expressed genes identified herein can be used to screen peptide libraries to identify binding partners, such as receptors, from among the encoded polypeptides. Peptide libraries can be synthesized according to methods known in the art (see, e.g., U.S. Pat. No. 5,010,175 and WO 91/17823).

Agonists or antagonists of the polypeptides of the invention can be screened using any available method known in the art, such as signal transduction, antibody binding, receptor binding, mitogenic assays, chemotaxis assays, etc. The assay conditions ideally should resemble the conditions under which the native activity is exhibited in vivo, that is, under physiologic pH, temperature, and ionic strength. Suitable agonists or antagonists will exhibit strong inhibition or enhancement of the native activity at concentrations that do not cause toxic side effects in the subject. Agonists or antagonists that compete for binding to the native polypeptide can require concentrations equal to or greater than the native concentration, while inhibitors capable of binding irreversibly to the polypeptide can be added in concentrations on the order of the native concentration.

Such screening and experimentation can lead to identification of a polypeptide binding partner, such as a receptor, encoded by a gene or a cDNA corresponding to a polynucleotide described herein, and at least one peptide agonist or antagonist of the binding partner. Such agonists and antagonists can be used to modulate, enhance, or inhibit receptor function in cells to which the receptor is native, or in cells that possess the receptor as a result of genetic engineering. Further, if the receptor shares biologically important characteristics with a known receptor, information about agonist/antagonist binding can facilitate development of improved agonists/antagonists of the known receptor.

Vaccines and Uses

The differentially expressed nucleic acids and polypeptides produced by the nucleic acids of the invention can also be used to modulate primary immune response to prevent or treat cancer. Every immune response is a complex and intricately regulated sequence of events involving several cell types. It is triggered when an antigen enters the body and encounters a specialized class of cells called antigen-presenting cells (APCs). These APCs capture a minute amount of the antigen and display it in a form that can be recognized by antigen-specific helper T lymphocytes. The helper (Th) cells become activated and, in turn, promote the activation of other classes of lymphocytes, such as B cells or cytotoxic T cells. The activated lymphocytes then proliferate and carry out their specific effector functions, which in many cases successfully activate or eliminate the antigen. Thus, activating the immune response to a particular antigen associated with a cancer cell can protect the patient from developing cancer or result in lymphocytes eliminating cancer cells expressing the antigen.

Gene products, including polypeptides, mRNA (particularly mRNAs having distinct secondary and/or tertiary structures), cDNA, or complete gene, can be prepared and used in vaccines for the treatment or prevention of hyperproliferative disorders and cancers. The nucleic acids and polypeptides can be utilized to enhance the immune response, prevent tumor progression, prevent hyperproliferative cell growth, and the like. Methods for selecting nucleic acids and polypeptides that are capable of enhancing the immune response are known in the art. Preferably, the gene products for use in a vaccine are gene products which are present on the surface of a cell and are recognizable by lymphocytes and antibodies.

The gene products may be formulated with pharmaceutically acceptable carriers into pharmaceutical compositions by methods known in the art. The composition is useful as a vaccine to prevent or treat cancer. The composition may further comprise at least one co-immunostimulatory molecule, including but not limited to one or more major histocompatibility complex (MHC) molecules, such as a class I or class II molecule, preferably a class I molecule. The composition may further comprise other stimulator molecules including B7.1, B7.2, ICAM-1, ICAM-2, LFA-1, LFA-3, CD72 and the like, immunostimulatory polynucleotides (which comprise an 5′-CG-3′ wherein the cytosine is unmethylated), and cytokines which include but are not limited to IL-1 through IL-15, TNF-α, IFN-γ, RANTES, G-CSF, M-CSF, IFN-α, CTAP III, ENA-78, GRO, I-309, PF-4, IP-10, LD-78, MGSA, MIP-1α, MIP-1β, or combination thereof, and the like for immunopotentiation. In one embodiment, the immunopotentiators of particular interest are those that facilitate a Th1 immune response.

The gene products may also be prepared with a carrier that will protect the gene products against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and the like. Methods for preparation of such formulations are known in the art.

In the methods of preventing or treating cancer, the gene products may be administered via one of several routes including but not limited to transdermal, transmucosal, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, intrapleural, intrauterine, rectal, vaginal, topical, intratumor, and the like. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, administration bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration may be by nasal sprays or suppositories. For oral administration, the gene products are formulated into conventional oral administration form such as capsules, tablets, elixirs and the like.

The gene product is administered to a patient in an amount effective to prevent or treat cancer. In general, it is desirable to provide the patient with a dosage of gene product of at least about 1 pg per Kg body weight, preferably at least about 1 ng per Kg body weight, more preferably at least about 1 μg or greater per Kg body weight of the recipient. A range of from about 1 ng per Kg body weight to about 100 mg per Kg body weight is preferred although a lower or higher dose may be administered. The dose is effective to prime, stimulate and/or cause the clonal expansion of antigen-specific T lymphocytes, preferably cytotoxic T lymphocytes, which in turn are capable of preventing or treating cancer in the recipient. The dose is administered at least once and may be provided as a bolus or a continuous administration. Multiple administrations of the dose over a period of several weeks to months may be preferable. Subsequent doses may be administered as indicated.

In another method of treatment, autologous cytotoxic lymphocytes or tumor infiltrating lymphocytes may be obtained from a patient with cancer. The lymphocytes are grown in culture, and antigen-specific lymphocytes are expanded by culturing in the presence of the specific gene products alone or in combination with at least one co-immunostimulatory molecule with cytokines. The antigen-specific lymphocytes are then infused back into the patient in an amount effective to reduce or eliminate the tumors in the patient. Cancer vaccines and their uses are further described in U.S. Pat. No. 5,961,978; U.S. Pat. No. 5,993,829; U.S. Pat. No. 6,132,980; and WO 00/38706.

Pharmaceutical Compositions and Uses

Pharmaceutical compositions can comprise polypeptides, receptors that specifically bind a polypeptide produced by a differentially expressed gene (e.g., antibodies, or polynucleotides (including antisense nucleotides and ribozymes) of the claimed invention in a therapeutically effective amount. The compositions can be used to treat primary tumors as well as metastases of primary tumors. In addition, the pharmaceutical compositions can be used in conjunction with conventional methods of cancer treatment, e.g., to sensitize tumors to radiation or conventional chemotherapy.

Where the pharmaceutical composition comprises a receptor (such as an antibody) that specifically binds to a gene product encoded by a differentially expressed gene, the receptor can be coupled to a drug for delivery to a treatment site or coupled to a detectable label to facilitate imaging of a site comprising cancer cells. Methods for coupling antibodies to drugs and detectable labels are well known in the art, as are methods for imaging using detectable labels.

The term “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect. The effect can be detected by, for example, chemical markers or antigen levels. Therapeutic effects also include reduction in physical symptoms, such as decreased body temperature.

The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance. However, the effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. For purposes of the present invention, an effective dose will generally be from about 0.01 mg/kg to 50 mg/kg or 0.05 mg/kg to about 10 mg/kg of the DNA constructs in the individual to which it is administered.

A pharmaceutical composition can also contain a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” refers to a carrier for administration of a therapeutic agent, such as antibodies or a polypeptide, genes, and other therapeutic agents. The term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates and inactive virus particles. Such carriers are well known to those of ordinary skill in the art. Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, can also be present in such vehicles.

Typically, the therapeutic compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. Liposomes are included within the definition of a pharmaceutically acceptable carrier. Pharmaceutically acceptable salts can also be present in the pharmaceutical composition, e.g., mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable excipients is available in Remington: The Science and Practice of Pharmacy (1995) Alfonso Gennaro, Lippincott, Williams, & Wilkins.

Delivery Methods

Once formulated, the compositions contemplated by the invention can be (1) administered directly to the subject (e.g., as polynucleotide, polypeptides, small molecule agonists or antagonists, and the like); or (2) delivered ex vivo, to cells derived from the subject (e.g., as in ex vivo gene therapy). Direct delivery of the compositions will generally be accomplished by parenteral injection, e.g., subcutaneously, intraperitoneally, intravenously or intramuscularly, intratumoral or to the interstitial space of a tissue. Other modes of administration include oral and pulmonary administration, suppositories, and transdermal applications, needles, and gene guns or hyposprays. Dosage treatment can be a single dose schedule or a multiple dose schedule.

Methods for the ex vivo delivery and reimplantation of transformed cells into a subject are known in the art and described in e.g., International Publication No. WO 93/14778. Examples of cells useful in ex vivo applications include, for example, stem cells, particularly hematopoetic, lymph cells, macrophages, dendritic cells, or tumor cells. Generally, delivery of nucleic acids for both ex vivo and in vitro applications can be accomplished by, for example, dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei, all well known in the art.

Once differential expression of a gene corresponding to a polynucleotide described herein has been found to correlate with a proliferative disorder, such as neoplasia, dysplasia, and hyperplasia, the disorder can be amenable to treatment by administration of a therapeutic agent based on the provided polynucleotide, corresponding polypeptide or other corresponding molecule (e.g., antisense, ribozyme, etc.). In other embodiments, the disorder can be amenable to treatment by administration of a small molecule drug that, for example, serves as an inhibitor (antagonist) of the function of the encoded gene product of a gene having increased expression in cancerous cells relative to normal cells or as an agonist for gene products that are decreased in expression in cancerous cells (e.g., to promote the activity of gene products that act as tumor suppressors).

The dose and the means of administration of the inventive pharmaceutical compositions are determined based on the specific qualities of the therapeutic composition, the condition, age, and weight of the patient, the progression of the disease, and other relevant factors. For example, administration of polynucleotide therapeutic composition agents includes local or systemic administration, including injection, oral administration, particle gun or catheterized administration, and topical administration. In general, the therapeutic polynucleotide composition contains an expression construct comprising a promoter operably linked to a polynucleotide of at least 12, 22, 25, 30, or 35 contiguous nt of the polynucleotide disclosed herein. Various methods can be used to administer the therapeutic composition directly to a specific site in the body. For example, a small metastatic lesion is located and the therapeutic composition injected several times in several different locations within the body of the tumor. Alternatively, arteries which serve a tumor are identified, and the therapeutic composition injected into such an artery, in order to deliver the composition directly into the tumor. A tumor that has a necrotic center is aspirated and the composition injected directly into the now empty center of the tumor. The antisense composition is directly administered to the surface of the tumor, for example, by topical application of the composition. X-ray imaging is used to assist in certain of the above delivery methods.

Targeted delivery of therapeutic compositions containing an antisense polynucleotide, subgenomic polynucleotides, or antibodies to specific tissues can also be used. Receptor-mediated DNA delivery techniques are described in, for example, Findeis et al., Trends Biotechnol. (1993) 11:202; Chiou et al., Gene Therapeutics: Methods And Applications Of Direct Gene Transfer (J. A. Wolff, ed.) (1994); Wu et al., J. Biol. Chem. (1988) 263:621; Wu et al., J. Biol. Chem. (1994) 269:542; Zenke et al., Proc. Natl. Acad. Sci. (USA) (1990) 87:3655; Wu et al., J. Biol. Chem. (1991) 266:338. Therapeutic compositions containing a polynucleotide are administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. Concentration ranges of about 500 ng to about 50 mg, about 1 μg to about 2 mg, about 5 μg to about 500 μg, and about 20 μg to about 100: g of DNA can also be used during a gene therapy protocol. Factors such as method of action (e.g., for enhancing or inhibiting levels of the encoded gene product) and efficacy of transformation and expression are considerations that will affect the dosage required for ultimate efficacy of the antisense subgenomic polynucleotides.

The therapeutic polynucleotides and polypeptides of the present invention can be delivered using gene delivery vehicles. The gene delivery vehicle can be of viral or non-viral origin (see generally, Jolly, Cancer Gene Therapy (1994) 1:51; Kimura, Human Gene Therapy (1994) 5:845; Connelly, Human Gene Therapy (1995) 1:185; and Kaplitt, Nature Genetics (1994) 6:148). Expression of such coding sequences can be induced using endogenous mammalian or heterologous promoters. Expression of the coding sequence can be either constitutive or regulated.

Viral-based vectors for delivery of a desired polynucleotide and expression in a desired cell are well known in the art. Exemplary viral-based vehicles include, but are not limited to, recombinant retroviruses (see, e.g., WO 90/07936; WO 94/03622; WO 93/25698; WO 93/25234; U.S. Pat. No. 5,219,740; WO 93/11230; WO 93/10218; U.S. Pat. No. 4,777,127; GB Patent No. 2,200,651; EP 0 345 242; and WO 91/02805), alphavirus-based vectors (e.g., Sindbis virus vectors, Semliki forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532), and adeno-associated virus (AAV) vectors (see, e.g., WO 94/12649, WO 93/03769; WO 93/19191; WO 94/28938; WO 95/11984 and WO 95/00655). Administration of DNA linked to killed adenovirus as described in Curiel, Hum. Gene Ther. (1992) 3:147 can also be employed.

Non-viral delivery vehicles and methods can also be employed, including, but not limited to, polycationic condensed DNA linked or unlinked to killed adenovirus alone (see, e.g., Curiel, Hum. Gene Ther. (1992) 3:147); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem. (1989) 264:16985); eukaryotic cell delivery vehicles cells (see, e.g., U.S. Pat. No. 5,814,482; WO 95/07994; WO 96/17072; WO 95/30763; and WO 97/42338) and nucleic charge neutralization or fusion with cell membranes. Naked DNA can also be employed. Exemplary naked DNA introduction methods are described in WO 90/11092 and U.S. Pat. No. 5,580,859. Liposomes that can act as gene delivery vehicles are described in U.S. Pat. No. 5,422,120; WO 95/13796; WO 94/23697; WO 91/14445; and EP 0524968. Additional approaches are described in Philip, Mol. Cell Biol. (1994) 14:2411, and in Woffendin, Proc. Natl. Acad. Sci. (1994) 91:1581.

The sequences disclosed in this patent application were disclosed in several earlier patent applications. The relationship between the SEQ ID NOS in those earlier application and the SEQ ID NOS disclosed herein is shown in Tables 161 and 162.

TABLE 161 relationship between SEQ ID NOs. this patent application and SEQ ID NOs of parent patent applications SEQ IDs corresponding parent parent in parent SEQ IDs in this case application no. filing date case patent application 1480 10/076,555 Feb. 15, 2002 1-844   1-844 1481 09/297,648 Mar. 10, 2000 1-5252  845-6096 1487 09/313,292 May 13, 1999 1-2707 6097-8803 1490 09/854,124 May 10, 2001 1-37  8804-8840 1492 09/404,706 Sep. 23, 1999 1-1079 8841-9919 1598 10/629,771 Jul. 28, 2003 1-3351  9920-13270 1624 09/803,719 Mar. 9, 2001 1-2396 13271-15666 1625 10/609,021 Jun. 26, 2003 1-324  15667-15990 15990 10/615,618 Jul. 7, 2003 1-6010 15991-22000 16252 10/012,697 Dec. 7, 2001 1-1568 22001-23568 18790 60/532,830 Dec. 23, 2003 1-199  23569-23767

The disclosures of all prior U.S. applications to which the present application claims priority, which includes those U.S. applications referenced in the table above as well as their respective priority applications, are each incorporated herein by referenced in their entireties for all purposes, including the disclosures found in the Sequence Listings, tables, figures and Examples.

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

Example 1 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

Human colon cancer cell line Km12L4-A (Morika, W. A. K. et al., Cancer Research (1988) 48:6863) was used to construct a cDNA library from mRNA isolated from the cells. As described in the above overview, a total of 4,693 sequences expressed by the Km12L4-A cell line were isolated and analyzed; most sequences were about 275-300 nucleotides in length. The KM12L4-A cell line is derived from the KM12C cell line. The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246).

The sequences were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate of relative little interest due to their lox complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of 43 sequences. The remaining sequences were then used in a BLASTN vs. Genbank search with search parameters of greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰, which search resulted in the discarding of 1,432 sequences. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the Genbank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). This search resulted in discard of 98 sequences as having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search resulted in discard of 1771 sequences (sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰; sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded). Second, a BLASTN vs. Patent GeneSeq database resulted in discard of 15 sequences (greater than 99% identity; p value less than 1×10⁻⁴⁰; greater than 99% overlap).

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 404 sequences listed in the accompanying Sequence Listing. The Sequence Listing is arranged beginning with sequences with no similarity to any sequence in a database searched, and ending with sequences with the greatest similarity. Each identified polynucleotide represents sequence from at least a partial mRNA transcript. Polynucleotides that were determined to be novel were assigned a sequence identification number.

The novel polynucleotides and were assigned sequence identification numbers SEQ ID NOS: 1-404. The DNA sequences corresponding to the novel polynucleotides are provided in the Sequence Listing. The majority of the sequences are presented in the Sequence Listing in the 5′ to 3′ direction. A small number, 25, are listed in the Sequence Listing in the 5′ to 3′ direction but the sequence as written is actually 3′ to 5′. These sequences are readily identified with the designation “AR” in the Sequence Name in Table 1 (inserted before the claims). The sequences correctly listed in the 5′ to 3′ direction in the Sequence Listing are designated “AF.” The Sequence Listing filed herewith therefore contains 25 sequences listed in the reverse order, namely SEQ ID NOS:47, 97, 137, 171, 173, 179, 182, 194, 200, 202, 213, 227, 258, 264, 275, 302, 313, 324, 329, 330, 331, 338, 358, 379, and 404.

Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene.

In order to confirm the sequences of SEQ ID NOS:1-404, inserts of the clones corresponding to these polynucleotides were re-sequenced. These “validation” sequences are provided in SEQ ID NOS:405-800. These validation sequences were often longer than the original polynucleotide sequences. They validate, and thus often provide additional sequence information. Validation sequences can be correlated with the original sequences they validate by identifying those sequences of SEQ ID NOS:1-404 and the validation sequences of SEQ ID NOS:405-800 that share the same clone name in Table 1.

TABLE 1 Sequence identification numbers, cluster ID, sequence name, and clone name SEQ ID NO: Cluster ID Sequence Name Clone Name 1 4635 RTA00000180AF.i.20.1 M00001429B:A11 2 RTA00000185AF.n.12.1 M00001608D:A11 3 4622 RTA00000187AF.m.15.2 M00001686A:E06 4 3706 RTA00000191AF.i.17.2 M00004068B:A01 5 36535 RTA00000181AF.f.5.1 M00001449A:G10 6 3990 RTA00000183AF.j.11.1 M00001532B:A06 7 5319 RTA00000192AF.i.12.1 M00004169C:C12 8 36393 RTA00000180AF.c.2.1 M00001417A:E02 9 2623 RTA00000183AF.a.6.1 M00001497A:G02 10 7587 RTA00000178AF.n.24.1 M00001387B:G03 11 7065 RTA00000137A.g.6.1 M00001557A:D02 12 10539 RTA00000187AF.l.7.1 M00001680D:F08 13 27250 RTA00000181AF.g.10.1 M00001450A:D08 14 5556 RTA00000179AF.n.10.1 M00001407B:D11 15 RTA00000192AF.m.12.1 M00004191D:B11 16 8761 RTA00000184AF.k.12.1 M00001557D:D09 17 4622 RTA00000189AF.g.1.1 M00003856B:C02 18 11460 RTA00000187AF.g.12.1 M00001676B:F05 19 16283 RTA00000120A.o.20.1 M00001467A:D08 20 3430 RTA00000191AF.a.9.1 M00003981A:E10 21 7065 RTA00000184AF.j.21.1 M00001557A:D02 22 RTA00000182AF.l.20.1 M00001488B:F12 23 RTA00000123A.g.19.1 M00001531A:H11 24 16918 RTA00000193AF.a.16.1 M00004223A:G10 25 16914 RTA00000193AF.f.5.1 M00004275C:C11 26 40108 RTA00000187AF.o.24.1 M00003741D:C09 27 14286 RTA00000193AF.f.22.1 M00004283B:A04 28 17004 RTA00000186AF.b.21.1 M00001617C:E02 29 RTA00000180AF.g.22.1 M00001426B:D12 30 13272 RTA00000192AF.e.3.1 M00004138B:H02 31 RTA00000194AF.f.4.1 M00005180C:G03 32 32663 RTA00000118A.l.8.1 M00001450A:A11 33 RTA00000180AF.a.9.1 M00001414A:B01 34 5832 RTA00000178AF.o.23.1 M00001388D:G05 35 7801 RTA00000181AF.c.21.1 M00001446A:F05 36 76760 RTA00000187AF.a.15.1 M00001657D:F08 37 40132 RTA00000178AF.c.7.1 M00001365C:C10 38 RTA00000183AF.e.1.1 M00001505C:C05 39 4016 RTA00000118A.c.4.1 M00001395A:C03 40 5382 RTA00000187AF.m.23.2 M00001688C:F09 41 5693 RTA00000190AF.p.17.2 M00003978B:G05 42 307 RTA00000136A.o.4.2 M00001552A:B12 43 39833 RTA00000178AF.i.23.1 M00001378B:B02 44 RTA00000193AF.m.5.1 M00004359B:G02 45 5325 RTA00000191AF.o.6.1 M00004093D:B12 46 5325 RTA00000191AF.o.6.2 M00004093D:B12 47 18957 RTA00000190AR.m.9.1 M00003958A:H02 48 39508 RTA00000120A.o.2.1 M00001467A:D04 49 22390 RTA00000136A.j.13.1 M00001551A:G06 50 12170 RTA00000125A.h.18.4 M00001544A:E03 51 4393 RTA00000187AF.n.17.1 M00001693C:G01 52 19 RTA00000182AF.b.7.1 M00001463C:B11 53 RTA00000193AF.c.21.1 M00004249D:F10 54 7899 RTA00000189AF.c.10.1 M00003837D:A01 55 40073 RTA00000191AF.e.3.1 M00004028D:C05 56 7005 RTA00000179AF.o.22.1 M00001410A:D07 57 RTA00000187AF.h.22.1 M00001679A:F06 58 18957 RTA00000190AF.m.9.2 M00003958A:H02 59 18957 RTA00000183AF.h.23.1 M00001528A:F09 60 16283 RTA00000182AF.c.22.1 M00001467A:D08 61 6974 RTA00000183AF.d.9.1 M00001504C:H06 62 2623 RTA00000183AF.b.14.1 M00001500A:E11 63 9105 RTA00000191AF.a.21.2 M00003983A:A05 64 13238 RTA00000181AF.m.4.1 M00001455A:E09 65 5749 RTA00000185AF.a.19.1 M00001571C:H06 66 6455 RTA00000193AF.b.9.1 M00004229B:F08 67 23001 RTA00000185AF.c.24.1 M00001578B:E04 68 6455 RTA00000192AF.g.23.1 M00004157C:A09 69 13595 RTA00000189AF.f.8.1 M00003851B:D10 70 39442 RTA00000120A.o.21.1 M00001467A:E10 71 17036 RTA00000191AF.f.13.1 M00004035D:B06 72 RTA00000183AF.g.9.1 M00001513B:G03 73 7005 RTA00000181AF.k.24.1 M00001454B:C12 74 6268 RTA00000126A.o.23.1 M00001551A:B10 75 16130 RTA00000119A.c.13.1 M00001453A:E11 76 23201 RTA00000187AF.a.14.1 M00001657D:C03 77 5321 RTA00000183AF.k.8.1 M00001534A:F09 78 13157 RTA00000186AF.a.6.1 M00001614C:F10 79 2102 RTA00000193AF.n.7.1 M00004377C:F05 80 1058 RTA00000126A.e.20.3 M00001548A:H09 81 40392 RTA00000180AF.j.8.1 M00001429D:D07 82 RTA00000183AF.e.23.1 M00001506D:A09 83 11476 RTA00000187AF.p.19.1 M00003747D:C05 84 3584 RTA00000177AF.h.20.1 M00001349B:B08 85 10470 RTA00000180AF.f.18.1 M00001424B:G09 86 39425 RTA00000133A.f.1.1 M00001470A:C04 87 5175 RTA00000184AF.f.3.1 M00001550A:G01 88 13576 RTA00000189AF.o.13.1 M00003885C:A02 89 7665 RTA00000134A.l.19.1 M00001535A:B01 90 16927 RTA00000177AF.h.9.3 M00001348B:B04 91 6660 RTA00000187AF.h.15.1 M00001679A:A06 92 2433 RTA00000191AF.a.15.2 M00003982C:C02 93 5097 RTA00000134A.k.1.1 M00001534A:D09 94 21847 RTA00000193AF.j.9.1 M00004318C:D10 95 3277 RTA00000138A.l.5.1 M00001624A:B06 96 5708 RTA00000184AF.g.12.1 M00001552B:D04 97 945 RTA00000178AR.a.20.1 M00001362C:H11 98 16269 RTA00000178AF.p.1.1 M00001389A:C08 99 RTA00000183AF.c.24.1 M00001504A:E01 100 16731 RTA00000181AF.a.20.1 M00001442C:D07 101 12439 RTA00000190AF.o.24.1 M00003975A:G11 102 3162 RTA00000177AF.j.12.3 M00001351B:A08 103 RTA00000194AF.b.19.1 M00004505D:F08 104 RTA00000193AF.n.15.1 M00004384C:D02 105 RTA00000186AF.n.7.1 M00001651A:H01 106 10717 RTA00000181AF.d.10.1 M00001447A:G03 107 4573 RTA00000189AF.j.12.1 M00003871C:E02 108 RTA00000186AF.h.14.1 M00001632D:H07 109 11443 RTA00000192AF.l.13.2 M00004185C:C03 110 5892 RTA00000184AF.d.11.1 M00001548A:E10 111 3162 RTA00000177AF.j.12.1 M00001351B:A08 112 10470 RTA00000185AF.k.6.1 M00001597D:C05 113 17055 RTA00000187AF.m.3.1 M00001682C:B12 114 2030 RTA00000193AF.m.20.1 M00004372A:A03 115 6558 RTA00000184AF.m.21.1 M00001560D:F10 116 23255 RTA00000190AF.j.4.1 M00003922A:E06 117 9577 RTA00000179AF.o.17.1 M00001409C:D12 118 RTA00000180AF.a.11.1 M00001414C:A07 119 8 RTA00000181AF.e.17.1 M00001448D:C09 120 67907 RTA00000188AF.g.11.1 M00003774C:A03 121 12081 RTA00000133A.d.14.2 M00001469A:C10 122 2448 RTA00000119A.j.21.1 M00001460A:F06 123 3389 RTA00000189AF.g.3.1 M00003857A:G10 124 39174 RTA00000124A.n.13.1 M00001541A:H03 125 24488 RTA00000190AF.n.16.1 M00003968B:F06 126 8210 RTA00000192AF.n.13.1 M00004197D:H01 127 RTA00000135A.l.2.2 M00001545A:B02 128 40455 RTA00000190AF.m.10.2 M00003958C:G10 129 9577 RTA00000180AF.d.23.1 M00001421C:F01 130 13183 RTA00000192AF.a.24.1 M00004114C:F11 131 5214 RTA00000186AF.g.11.1 M00001630B:H09 132 67252 RTA00000187AF.o.6.1 M00001716D:H05 133 3108 RTA00000188AF.d.24.1 M00003763A:F06 134 2464 RTA00000178AF.n.18.1 M00001387A:C05 135 36313 RTA00000181AF.e.23.1 M00001448D:H01 136 23255 RTA00000177AF.e.14.3 M00001343D:H07 137 7985 RTA00000182AR.j.2.1 M00001481D:A05 138 8286 RTA00000183AF.o.1.1 M00001540A:D06 139 22195 RTA00000180AF.g.7.1 M00001425B:H08 140 4573 RTA00000184AF.h.9.1 M00001553B:F12 141 26875 RTA00000187AF.i.1.1 M00001679A:F10 142 7187 RTA00000177AF.i.8.2 M00001350A:H01 143 86859 RTA00000118A.p.8.1 M00001452A:B12 144 4623 RTA00000185AF.f.4.1 M00001586C:C05 145 RTA00000121A.c.10.1 M00001469A:A01 146 10185 RTA00000183AF.d.5.1 M00001504C:A07 147 RTA00000183AF.p.4.1 M00001542B:B01 148 15069 RTA00000191AF.l.6.1 M00004081C:D10 149 39304 RTA00000118A.j.21.1 M00001450A:A02 150 8672 RTA00000190AF.f.11.1 M00003909D:C03 151 13576 RTA00000177AF.g.16.1 M00001347A:B10 152 6293 RTA00000185AF.e.11.1 M00001583D:A10 153 16977 RTA00000192AF.g.3.1 M00004151D:B08 154 5345 RTA00000189AF.l.19.1 M00003879B:C11 155 4905 RTA00000193AF.e.14.1 M00004269D:D06 156 17036 RTA00000191AF.j.10.1 M00004072B:B05 157 5417 RTA00000191AF.h.19.1 M00004059A:D06 158 7172 RTA00000178AF.f.9.1 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RTA00000187AF.j.6.1 M00001679C:F01 271 39539 RTA00000127A.i.21.1 M00001555A:B02 272 RTA00000182AF.l.15.1 M00001487B:H06 273 RTA00000194AF.d.13.1 M00004896A:C07 274 RTA00000128A.c.20.1 M00001558A:H05 275 9283 RTA00000181AR.m.22.2 M00001455D:F09 276 39168 RTA00000121A.l.10.1 M00001507A:H05 277 39458 RTA00000126A.p.15.2 M00001552A:D11 278 14391 RTA00000177AF.m.17.3 M00001355B:G10 279 39195 RTA00000137A.c.16.1 M00001555A:C01 280 7212 RTA00000193AF.b.14.1 M00004230B:C07 281 4015 RTA00000136A.e.12.1 M00001549A:B02 282 12977 RTA00000189AF.j.19.1 M00003875B:F04 283 RTA00000178AF.m.13.1 M00001384B:A11 284 14391 RTA00000191AF.1.7.1 M00004081C:D12 285 RTA00000194AF.c.23.1 M00004691D:A05 286 RTA00000181AF.b.7.1 M00001443B:F01 287 8358 RTA00000183AF.i.5.1 M00001528B:H04 288 1267 RTA00000125A.o.5.1 M00001546A:G11 289 RTA00000189AF.f.7.1 M00003851B:D08 290 16347 RTA00000184AF.e.15.1 M00001549C:E06 291 7899 RTA00000193AF.a.17.1 M00004223B:D09 292 2379 RTA00000178AF.a.6.1 M00001361D:F08 293 39478 RTA00000133A.i.5.1 M00001471A:B01 294 39392 RTA00000134A.m.16.1 M00001536A:C08 295 5053 RTA00000184AF.o.12.1 M00001564A:B12 296 16999 RTA00000185AF.k.9.1 M00001598A:G03 297 39180 RTA00000126A.n.8.2 M00001551A:F05 298 1037 RTA00000121A.f.8.1 M00001470A:B10 299 6867 RTA00000178AF.e.12.1 M00001370A:C09 300 10539 RTA00000183AF.a.24.1 M00001499B:A11 301 41633 RTA00000118A.g.16.1. M00001449A:B12 302 23218 RTA00000187AR.c.5.2 M00001662C:A09 303 39380 RTA00000129A.e.24.1 M00001587A:B11 304 RTA00000185AF.d.24.1 M00001582D:F05 305 RTA00000177AF.o.4.3 M00001358C:C06 306 6974 RTA00000184AF.a.15.1 M00001544B:B07 307 RTA00000185AF.g.11.1 M00001590B:F03 308 15855 RTA00000184AF.j.1.1 M00001556A:H01 309 84328 RTA00000118A.p.10.1 M00001452A:B04 310 10145 RTA00000120A.g.12.1 M00001465A:B11 311 39805 RTA00000177AF.c.21.3 M00001342B:E06 312 RTA00000187AF.h.23.1 M00001679A:F06 313 6298 RTA00000187AR.i.10.2 M00001679B:F01 314 14367 RTA00000187AF.e.8.1 M00001670C:H02 315 RTA00000193AF.c.22.1 M00004249D:G12 316 16921 RTA00000183AF.k.6.1 M00001534A:C04 317 1577 RTA00000184AF.i.23.1 M00001556A:F11 318 8773 RTA00000187AF.f.24.1 M00001675A:C09 319 RTA00000194AF.a.11.1 M00004461A:B09 320 39886 RTA00000178AF.j.24.1 M00001380D:B09 321 13532 RTA00000181AF.c.4.1 M00001445A:F05 322 RTA00000193AF.d.2.1 M00004251C:G07 323 5257 RTA00000192AF.f.3.1 M00004146C:C11 324 9061 RTA00000191AR.e.11.2 M00004031A:A12 325 19267 RTA00000186AF.1.12.1 M00001645A:C12 326 20212 RTA00000134A.1.22.1 M00001535A:C06 327 16653 RTA00000181AF.k.5.3 M00001453C:F06 328 16985 RTA00000177AF.h.10.1 M00001348B:G06 329 12977 RTA00000189AR.j.19.1 M00003875B:F04 330 9061 RTA00000191AR.e.11.3 M00004031A:A12 331 RTA00000194AR.a.10.2 M00004461A:B08 332 6468 RTA00000187AF.d.15.1 M00001669B:F02 333 16392 RTA00000192AF.1.1.1 M00004183C:D07 334 14627 RTA00000187AF.g.23.1 M00001677C:E10 335 6583 RTA00000179AF.d.13.1 M00001394A:F01 336 6806 RTA00000177AF.g.13.3 M00001346D:E03 337 9635 RTA00000137A.e.23.4 M00001557A:F01 338 689 RTA00000181AR.1.22.1 M00001454D:G03 339 4119 RTA00000183AF.k.16.1 M00001534C:A01 340 8952 RTA00000183AF.h.15.1 M00001518C:B11 341 2379 RTA00000192AF.p.8.1 M00004212B:C07 342 39486 RTA00000128A.m.22.2 M00001561A:C05 343 21877 RTA00000189AF.b.21.1 M00003833A:E05 344 6874 RTA00000192AF.a.14.1 M00004111D:A08 345 6874 RTA00000189AF.e.9.1 M00003846B:D06 346 37285 RTA00000191AF.f.11.1 M00004035C:A07 347 RTA00000193AF.j.20.1 M00004327B:H04 348 7674 RTA00000118A.g.9.1 M00001416A:H01 349 2797 RTA00000180AF.i.19.1 M00001429A:H04 350 RTA00000184AF.g.22.1 M00001552D:A01 351 7802 RTA00000185AF.n.5.1 M00001608A:B03 352 16921 RTA00000193AF.h.15.1 M00004295D:F12 353 11494 RTA00000192AF.j.6.1 M00004172C:D08 354 17062 RTA00000177AF.b.8.4 M00001340B:A06 355 16245 RTA00000177AF.k.9.3 M00001352A:E02 356 83103 RTA00000119A.e.24.2 M00001454A:A09 357 4309 RTA00000186AF.e.22.1 M00001624C:F01 358 13072 RTA00000181AR.m.5.2 M00001455B:E12 359 4059 RTA00000177AF.n.18.3 M00001357D:D11 360 5178 RTA00000178AF.n.10.1 M00001386C:B12 361 1120 RTA00000118A.p.15.3 M00001452A:D08 362 6420 RTA00000183AF.d.11.1 M00001504D:G06 363 13913 RTA00000186AF.e.6.1 M00001623D:F10 364 RTA00000192AF.c.2.1 M00004121B:G01 365 3956 RTA00000183AF.g.3.1 M00001512D:G09 366 14364 RTA00000183AF.g.12.1 M00001513C:E08 367 6880 RTA00000191AF.m.20.1 M00004087D:A01 368 84182 RTA00000180AF.h.19.1 M00001428A:H10 369 2790 RTA00000177AF.e.2.1 M00001343C:F10 370 4561 RTA00000184AF.i.21.1 M00001555D:G10 371 8847 RTA00000180AF.b.16.1 M00001416B:H11 372 56020 RTA00000193AF.g.2.1 M00004285B:E08 373 1531 RTA00000119A.o.3.1 M00001461A:D06 374 6420 RTA00000177AF.f.10.3 M00001345A:E01 375 RTA00000188AF.b.12.1 M00003754C:E09 376 RTA00000180AF.k.24.1 M00001432C:F06 377 RTA00000184AF.a.8.1 M00001544A:E06 378 2696 RTA00000134A.m.13.1 M00001536A:B07 379 260 RTA00000185AR.i.12.2 M00001594B:H04 380 11350 RTA00000189AF.a.24.2 M00003826B:A06 381 2428 RTA00000123A.l.21.1 M00001533A:C11 382 4313 RTA00000122A.n.3.1 M00001517A:B07 383 RTA00000184AF.p.3.1 M00001566B:D11 384 697 RTA00000188AF.d.6.1 M00003759B:B09 385 5619 RTA00000188AF.1.9.1 M00003796C:D05 386 4568 RTA00000122A.d.15.3 M00001513A:B06 387 RTA00000177AF.i.6.2 M00001350A:B08 388 5622 RTA00000178AF.a.11.1 M00001362B:D10 389 7514 RTA00000184AF.k.21.1 M00001558B:H11 390 5619 RTA00000189AF.f.17.1 M00003853A:D04 391 7570 RTA00000187AF.g.24.1 M00001677D:A07 392 23358 RTA00000190AF.o.21.1 M00003974D:H02 393 23210 RTA00000190AF.o.20.1 M00003974D:E07 394 5192 RTA00000184AF.k.2.1 M00001557B:H10 395 13538 RTA00000180AF.a.24.1 M00001415A:H06 396 RTA00000189AF.h.17.1 M00003867A:D10 397 RTA00000192AF.o.11.1 M00004205D:F06 398 RTA00000184AF.1.11.1 M00001559B:F01 399 4718 RTA00000189AF.g.5.1 M00003857A:H03 400 14929 RTA00000177AF.m.1.2 M00001353D:D10 401 4908 RTA00000192AF.j.2.1 M00004171D:B03 402 RTA00000178AF.k.16.1 M00001381D:E06 403 RTA00000194AF.c.24.1 M00004692A:H08 404 17732 RTA00000178AR.i.2.2 M00001376B:G06 405 17062 80.A1.sp6:130208.Seq M00001340B:A06 406 11589 80.B1.sp6:130220.Seq M00001340D:F10 407 4443 80.C1.sp6:130232.Seq M00001341A:E12 408 39805 80.D1.sp6:130244.Seq M00001342B:E06 409 2790 80.E1.sp6:130256.Seq M00001343C:F10 410 23255 80.F1.sp6:130268.Seq M00001343D:H07 411 6420 80.G1.sp6:130280.Seq M00001345A:E01 412 5007 80.H1.sp6:130292.Seq M00001346A:F09 413 13576 80.D2.sp6:130245.Seq M00001347A:B10 414 16927 80.E2.sp6:130257.Seq M00001348B:B04 415 16985 80.F2.sp6:130269.Seq M00001348B:G06 416 3584 80.G2.sp6:130281.Seq M00001349B:B08 417 80.H2.sp6:130293.Seq M00001350A:B08 418 7187 80.A3.sp6:130210.Seq M00001350A:H01 419 16245 80.D3.sp6:130246.Seq M00001352A:E02 420 8078 80.E3.sp6:130258.Seq M00001353A:G12 421 14929 80.F3.sp6:130270.Seq M00001353D:D10 422 14391 80.G3.sp6:130282.Seq M00001355B:G10 423 4141 80.B4.sp6:130223.Seq M00001361A:A05 424 2379 80.C4.sp6:130235.Seq M00001361D:F08 425 5622 80.D4.sp6:130247.Seq M00001362B:D10 426 945 80.E4.sp6:130259.Seq M00001362C:H11 427 40132 80.F4.sp6:130271.Seq M00001365C:C10 428 80.G4.sp6:130283.Seq M00001368D:E03 429 6867 80.H4.sp6:130295.Seq M00001370A:C09 430 7172 80.A5.sp6:130212.Seq M00001371C:E09 431 17732 80.B5.sp6:130224.Seq M00001376B:G06 432 39833 80.C5.sp6:130236.Seq M00001378B:B02 433 1334 80.D5.sp6:130248.Seq M00001379A:A05 434 39886 80.E5.sp6:130260.Seq M00001380D:B09 435 80.F5.sp6:130272.Seq M00001381D:E06 436 22979 80.G5.sp6:130284.Seq M00001382C:A02 437 39648 80.H5.sp6:130296.Seq M00001383A:C03 438 80.B6.sp6:130225.Seq M00001384B:A11 439 5178 80.C6.sp6:130237.Seq M00001386C:B12 440 2464 80.D6.sp6:130249.Seq M00001387A:C05 441 7587 80.E6.sp6:130261.Seq M00001387B:G03 442 5832 80.F6.sp6:130273.Seq M00001388D:G05 443 16269 80.G6.sp6:130285.Seq M00001389A:C08 444 6583 80.H6.sp6:130297.Seq M00001394A:F01 445 4009 80.A7.sp6:130214.Seq M00001396A:C03 446 80.B7.sp6:130226.Seq M00001400B:H06 447 39563 80.C7.sp6:130238.Seq M00001402A:E08 448 5556 80.D7.sp6:130250.Seq M00001407B:D11 449 9577 80.E7.sp6:130262.Seq M00001409C:D12 450 7005 80.F7.sp6:130274.Seq M00001410A:D07 451 8551 80.G7.sp6:130286.Seq M00001412B:B10 452 80.H7.sp6:130298.Seq M00001414A:B01 453 80.A8.sp6:130215.Seq M00001414C:A07 454 13538 80.B8.sp6:130227.Seq M00001415A:H06 455 8847 80.C8.sp6:130239.Seq M00001416B:H11 456 36393 80.D8.sp6:130251.Seq M00001417A:E02 457 9952 80.E8.sp6:130263.Seq M00001418B:F03 458 9577 80.G8.sp6:130287.Seq M00001421C:F01 459 15066 80.H8.sp6:130299.Seq M00001423B:E07 460 10470 80.A9.sp6:130216.Seq M00001424B:G09 461 22195 80.B9.sp6:130228.Seq M00001425B:H08 462 80.C9.sp6:130240.Seq M00001426B:D12 463 4261 80.D9.sp6:130252.Seq M00001426D:C08 464 84182 80.E9.sp6:130264.Seq M00001428A:H10 465 40392 80.H9.sp6:130300.Seq M00001429D:D07 466 16731 80.C10.sp6:130241.Seq M00001442C:D07 467 80.D10.sp6:130253.Seq M00001443B:F01 468 13532 80.E10.sp6:130265.Seq M00001445A:F05 469 8 80.H10.sp6:130301.Seq M00001448D:C09 470 36313 80.A11.sp6:130218.Seq M00001448D:H01 471 5857 80.B11.sp6:130230.Seq M00001449A:A12 472 41633 80.C11.sp6:130242.Seq M00001449A:B12 473 36535 80.D11.sp6:130254.Seq M00001449A:G10 474 86110 80.E11.sp6:130266.Seq M00001449C:D06 475 32663 80.F11.sp6:130278.Seq M00001450A:A11 476 27250 80.G11.sp6:130290.Seq M00001450A:D08 477 16970 80.H11.sp6:130302.Seq M00001452C:B06 478 16130 80.A12.sp6:130219.Seq M00001453A:E11 479 16653 80.B12.sp6:130231.Seq M00001453C:F06 480 7005 80.C12.sp6:130243.Seq M00001454B:C12 481 13072 80.F12.sp6:130279.Seq M00001455B:E12 482 9283 80.G12.sp6:130291.Seq M00001455D:F09 483 23255 100.C1.sp6:131446.Seq M00001343D:H07 484 13576 100.E1.sp6:131470.Seq M00001347A:B10 485 7187 100.C2.sp6:131447.Seq M00001350A:H01 486 14391 100.E3.sp6:131472.Seq M00001355B:G10 487 945 100.E4.sp6:131473.Seq M00001362G:H11 488 7172 100.A5.sp6:131426.Seq M00001371C:E09 489 39648 100.A6.sp6:131427.Seq M00001383A:C03 490 84182 100.G9.sp6:131502.Seq M00001428A:H10 491 8 100.B11.sp6:131444.Seq M00001448D:C09 492 36535 100.D11.sp6:131468.Seq M00001449A:G10 493 82498 100.F11.sp6:131492.Seq M00001450A:B12 494 16970 100.C12.sp6:131457.Seq M00001452C:B06 495 16130 100.D12.sp6:131469.Seq M00001453A:E11 496 7005 121.D1.sp6:131917.Seq M00001454B:C12 497 121.G6.sp6:131958.Seq M00001506D:A09 498 18957 121.F7.sp6:131947.Seq M00001528A:F09 499 40044 122.E1.sp6:132121.Seq M00001621C:C08 500 5214 122.C2.sp6:132098.Seq M00001630B:H09 501 6660 122.B5.sp6:132089.Seq M00001679A:A06 502 13183 123.D5.sp6:132305.Seq M00004114C:F11 503 6455 123.E7.sp6:132319.Seq M00004157C:A09 504 5319 123.F7.sp6:132331.Seq M00004169C:C12 505 11443 123.A8.sp6:132272.Seq M00004185C:C03 506 123.C8.sp6:132296.Seq M00004191D:B11 507 8210 123.E8.sp6:132320.Seq M00004197D:H01 508 9457 123.D11.sp6:132311.Seq M00004307C:A06 509 6420 172.E1.sp6:133925.Seq M00001345A:E01 510 16245 172.D2.sp6:133914.Seq M00001352A:E02 511 8078 172.C3.sp6:133903.Seq M00001353A:G12 512 14929 172.D3.sp6:133915.Seq M00001353D:D10 513 14391 172.H3.sp6:133963.Seq M00001355B:G10 514 6583 172.B8.sp6:133896.Seq M00001394A:F01 515 4009 172.D8.sp6:133920.Seq M00001396A:C03 516 172.B9.sp6:133897.Seq M00001400B:H06 517 176.A3.sp6:134514.Seq M00001632D:H07 518 19267 176.G3.sp6:134586.Seq M00001645A:C12 519 78091 176.G5.sp6:134588.Seq M00001679C:F01 520 17055 176.D6.sp6:134553.Seq M00001682C:B12 521 6539 176.D9.sp6:134556.Seq M00003844C:B11 522 177.H4.sp6:134791.Seq M00004121B:G01 523 5257 177.F5.sp6:134768.Seq M00004146C:C11 524 11494 177.E6.sp6:134757.Seq M00004172C:D08 525 177.G7.sp6:134782.Seq M00004205D:F06 526 11451 177.D8.sp6:134747.Seq M00004214C:H05 527 9283 173.D2.SP6:134106.Seq M00001455D:F09 528 16283 173.F3.SP6:134131.Seq M00001467A:D08 529 10539 173.B5.SP6:134085.Seq M00001499B:A11 530 6420 173.F5.SP6:134133.Seq M00001504D:G06 531 3956 173.H5.SP6:134157.Seq M00001512D:G09 532 173.G7.SP6:134147.Seq M00001544A:E06 533 1577 173.C9.SP6:134101.Seq M00001556A:F11 534 9635 173.D9.SP6:134113.Seq M00001557A:F01 535 5192 173.E9.SP6:134125.Seq M00001557B:H10 536 6539 173.A12.SP6:134080.Seq M00001579D:C03 537 945 180.C2.sp6:135940.Seq M00001362C:H11 538 7005 180.H5.sp6:136003.Seq M00001410A:D07 539 39304 180.G9.sp6:135995.Seq M00001450A:A02 540 27250 180.B10.sp6:135936.Seq M00001450A:D08 541 35555 184.A5.sp6:135530.Seq M00001528A:C04 542 19255 184.B10.sp6:135547.Seq M00001545A:C03 543 6268 184.C12.sp6:135561.Seq M00001551A:B10 544 3277 217.E1.sp6:139406.Seq M00001624A:B06 545 39171 217.A12.sp6:139369.Seq M00001644C:B07 546 11460 219.F2.sp6:139035.Seq M00001676B:F05 547 10539 219.F6.sp6:139039.Seq M00001680D:F08 548 11476 219.H8.sp6:139065.Seq M00003747D:C05 549 4016 79.A1.sp6:130016.Seq M00001395A:C03 550 7674 79.C1.sp6:130040.Seq M00001416A:H01 551 3681 79.E1.sp6:130064.Seq M00001449A:D12 552 39304 79.F1.sp6:130076.Seq M00001450A:A02 553 82498 79.G1.sp6:130088.Seq M00001450A:B12 554 84328 79.A2.sp6:130017.Seq M00001452A:B04 555 86859 79.B2.sp6:130029.Seq M00001452A:B12 556 1120 79.C2.sp6:130041.Seq M00001452A:D08 557 85064 79.D2.sp6:130053.Seq M00001452A:F05 558 83103 79.G2.sp6:130089.Seq M00001454A:A09 559 10145 79.F3.sp6:130078.Seq M00001465A:B11 560 16283 79.H3.sp6:130102.Seq M00001467A:D08 561 4568 79.D4.sp6:130055.Seq M00001513A:B06 562 4313 79.F4.sp6:130079.Seq M00001517A:B07 563 2428 79.A5.sp6:130020.Seq M00001533A:C11 564 39423 79.C5.sp6:130044.Seq M00001535A:F10 565 39174 79.E5.sp6:130068.Seq M00001541A:H03 566 22113 79.F5.sp6:130080.Seq M00001542A:A09 567 19829 79.H5.sp6:130104.Seq M00001544A:G02 568 13864 79.B6.sp6:130033.Seq M00001545A:D08 569 1058 79.F6.sp6:130081.Seq M00001548A:H09 570 4015 79.G6.sp6:130093.Seq M00001549A:B02 571 39180 79.A7.sp6:130022.Seq M00001551A:F05 572 307 79.C7.sp6:130046.Seq M00001552A:B12 573 39458 79.D7.sp6:130058.Seq M00001552A:D11 574 39490 79.G7.sp6:130094.Seq M00001557A:F03 575 39486 79.B8.sp6:130035.Seq M00001561A:C05 576 39380 79.E8.sp6:130071.Seq M00001587A:B11 577 1399 79.G8.sp6:130095.Seq M00001604A:B10 578 39391 79.A9.sp6:130024.Seq M00001604A:F05 579 6268 79.G9.sp6:130096.Seq M00001551A:B10 580 377.F4.sp6:141957.Seq M00004692A:H08 581 2448 89.A1.sp6:130667.Seq M00001460A:F06 582 1531 89.C1.sp6:130691.Seq M00001461A:D06 583 19 89.D1.sp6:130703.Seq M00001463C:B11 584 38759 89.F1.sp6:130727.Seq M00001467A:B07 585 39508 89.G1.sp6:130739.Seq M00001467A:D04 586 16283 89.H1.sp6:130751.Seq M00001467A:D08 587 39442 89.A2.sp6:130668.Seq M00001467A:E10 588 7589 89.B2.sp6:130680.Seq M00001468A:F05 589 89.C2.sp6:130692.Seq M00001469A:A01 590 12081 89.D2.sp6:130704.Seq M00001469A:C10 591 19105 89.E2.sp6:130716.Seq M00001469A:H12 592 1037 89.F2.sp6:130728.Seq M00001470A:B10 593 39425 89.G2.sp6:130740.Seq M00001470A:C04 594 39478 89.H2.sp6:130752.Seq M00001471A:B01 595 89.B3.sp6:130681.Seq M00001487B:H06 596 89.C3.sp6:130693.Seq M00001488B:F12 597 18699 89.D3.sp6:130705.Seq M00001490B:C04 598 7206 89.E3.sp6:130717.Seq M00001494D:F06 599 2623 89.F3.sp6:130729.Seq M00001497A:G02 600 10539 89.G3.sp6:130741.Seq M00001499B:A11 601 5336 89.H3.sp6:130753.Seq M00001500A:C05 602 2623 89.A4.sp6:130670.Seq M00001500A:E11 603 9443 89.B4.sp6:130682.Seq M00001500C:E04 604 9685 89.C4.sp6:130694.Seq M00001501D:C02 605 89.D4.sp6:130706.Seq M00001504A:E01 606 10185 89.E4.sp6:130718.Seq M00001504C:A07 607 6974 89.F4.sp6:130730.Seq M00001504C:H06 608 6420 89.G4.sp6:130742.Seq M00001504D:G06 609 89.H4.sp6:130754.Seq M00001505C:C05 610 89.A5.sp6:130671.Seq M00001506D:A09 611 39168 89.B5.sp6:130683.Seq M00001507A:H05 612 39412 89.C5.sp6:130695.Seq M00001511A:H06 613 39186 89.D5.sp6:130707.Seq M00001512A:A09 614 3956 89.E5.sp6:130719.Seq M00001512D:G09 615 89.F5.sp6:130731.Seq M00001513B:G03 616 14364 89.G5.sp6:130743.Seq M00001513C:E08 617 40044 89.H5.sp6:130755.Seq M00001514C:D11 618 8952 89.A6.sp6:130672.Seq M00001518C:B11 619 35555 89.B6.sp6:130684.Seq M00001528A:C04 620 18957 89.C6.sp6:130696.Seq M00001528A:F09 621 8358 89.D6.sp6:130708.Seq M00001528B:H04 622 38085 89.E6.sp6:130720.Seq M00001531A:D01 623 89.F6.sp6:130732.Seq M00001531A:H11 624 3990 89.G6.sp6:130744.Seq M00001532B:A06 625 16921 89.H6.sp6:130756.Seq M00001534A:C04 626 5321 89.B7.sp6:130685.Seq M00001534A:F09 627 4119 89.C7.sp6:130697.Seq M00001534C:A01 628 20212 89.E7.sp6:130721.Seq M00001535A:C06 629 2696 89.F7.sp6:130733.Seq M00001536A:B07 630 39392 89.G7.sp6:130745.Seq M00001536A:C08 631 39420 89.H7.sp6:130757.Seq M00001537A:F12 632 3389 89.A8.sp6:130674.Seq M00001537B:G07 633 8286 89.B8.sp6:130686.Seq M00001540A:D06 634 3765 89.C8.sp6:130698.Seq M00001541A:D02 635 39453 89.E8.sp6:130722.Seq M00001542A:E06 636 89.F8.sp6:130734.Seq M00001542B:B01 637 89.H8.sp6:130758.Seq M00001544A:E06 638 6974 89.A9.sp6:130675.Seq M00001544B:B07 639 89.B9.sp6:130687.Seq M00001545A:B02 640 19255 89.C9.sp6:130699.Seq M00001545A:C03 641 1267 89.D9.sp6:130711.Seq M00001546A:G11 642 5892 89.E9.sp6:130723.Seq M00001548A:E10 643 4193 89.G9.sp6:130747.Seq M00001549B:F06 644 16347 89.H9.sp6:130759.Seq M00001549C:E06 645 7239 89.A10.sp6:130676.Seq M00001550A:A03 646 5175 89.B10.sp6:130688.Seq M00001550A:G01 647 22390 89.C10.sp6:130700.Seq M00001551A:G06 648 3266 89.D10.sp6:130712.Seq M00001551C:G09 649 5708 89.E10.sp6:130724.Seq M00001552B:D04 650 89.F10.sp6:130736.Seq M00001552D:A01 651 8298 89.G10.sp6:130748.Seq M00001553A:H06 652 4573 89.H10.sp6:130760.Seq M00001553B:F12 653 22814 89.A11.sp6:130677.Seq M00001553D:D10 654 39539 89.B11.sp6:130689.Seq M00001555A:B02 655 39195 89.C11.sp6:130701.Seq M00001555A:C01 656 4561 89.D11.sp6:130713.Seq M00001555D:G10 657 9244 89.E11.sp6:130725.Seq M00001556A:C09 658 1577 89.F11.sp6:130737.Seq M00001556A:F11 659 4386 89.H11.sp6:130761.Seq M00001556B:C08 660 11294 89.A12.sp6:130678.Seq M00001556B:G02 661 5192 89.D12.sp6:130714.Seq M00001557B:H10 662 8761 89.E12.sp6:130726.Seq M00001557D:D09 663 89.F12.sp6:130738.Seq M00001558A:H05 664 7514 89.G12.sp6:130750.Seq M00001558B:H11 665 89.H12.sp6:130762.Seq M00001559B:F01 666 6558 90.A1.sp6:130859.Seq M00001560D:F10 667 102 90.B1.sp6:130871.Seq M00001563B:F06 668 90.D1.sp6:130895.Seq M00001566B:D11 669 5749 90.E1.sp6:130907.Seq M00001571C:H06 670 6539 90.G1.sp6:130931.Seq M00001579D:C03 671 6293 90.A2.sp6:130860.Seq M00001583D:A10 672 90.C2.sp6:130884.Seq M00001590B:F03 673 260 90.D2.sp6:130896.Seq M00001594B:H04 674 4837 90.E2.sp6:130908.Seq M00001597C:H02 675 10470 90.F2.sp6:130920.Seq M00001597D:C05 676 16999 90.G2.sp6:130932.Seq M00001598A:G03 677 22794 90.H2.sp6:130944.Seq M00001601A:D08 678 11465 90.A3.sp6:130861.Seq M00001607A:E11 679 7802 90.B3.sp6:130873.Seq M00001608A:B03 680 22155 90.C3.sp6:130885.Seq M00001608B:E03 681 90.D3.sp6:130897.Seq M00001608D:A11 682 13157 90.E3.sp6:130909.Seq M00001614C:F10 683 17004 90.F3.sp6:130921.Seq M00001617C:E02 684 40314 90.G3.sp6:130933.Seq M00001619C:F12 685 40044 90.H3.sp6:130945.Seq M00001621C:C08 686 13913 90.A4.sp6:130862.Seq M00001623D:F10 687 3277 90.B4.sp6:130874.Seq M00001624A:B06 688 4309 90.C4.sp6:130886.Seq M00001624C:F01 689 5214 90.D4.sp6:130898.Seq M00001630B:H09 690 90.E4.sp6:130910.Seq M00001632D:H07 691 39171 90.F4.sp6:130922.Seq M00001644C:B07 692 19267 90.G4.sp6:130934.Seq M00001645A:C12 693 4665 90.H4.sp6:130946.Seq M00001648C:A01 694 90.A5.sp6:130863.Seq M00001651A:H01 695 23201 90.B5.sp6:130875.Seq M00001657D:C03 696 76760 90.C5.sp6:130887.Seq M00001657D:F08 697 23218 90.D5.sp6:130899.Seq M00001662C:A09 698 35702 90.E5.sp6:130911.Seq M00001663A:E04 699 6468 90.F5.sp6:130923.Seq M00001669B:F02 700 14367 90.G5.sp6:130935.Seq M00001670C:H02 701 7015 90.H5.sp6:130947.Seq M00001673C:H02 702 8773 90.A6.sp6:130864.Seq M00001675A:C09 703 11460 90.B6.sp6:130876.Seq M00001676B:F05 704 7570 90.D6.sp6:130900.Seq M00001677D:A07 705 4416 90.E6.sp6:130912.Seq M00001678D:F12 706 6660 90.F6.sp6:130924.Seq M00001679A:A06 707 90.H6.sp6:130948.Seq M00001679A:F06 708 26875 90.A7.sp6:130865.Seq M00001679A:F10 709 6298 90.B7.sp6:130877.Seq M00001679B:F01 710 78091 90.C7.sp6:130889.Seq M00001679C:F01 711 10751 90.D7.sp6:130901.Seq M00001679D:D03 712 10539 90.F7.sp6:130925.Seq M00001680D:F08 713 17055 90.G7.sp6:130937.Seq M00001682C:B12 714 5382 90.A8.sp6:130866.Seq M00001688C:F09 715 4393 90.B8.sp6:130878.Seq M00001693C:G01 716 67252 90.C8.sp6:130890.Seq M00001716D:H05 717 40108 90.D8.sp6:130902.Seq M00003741D:C09 718 11476 90.E8.sp6:130914.Seq M00003747D:C05 719 90.F8.sp6:130926.Seq M00003754C:E09 720 697 90.G8.sp6:130938.Seq M00003759B:B09 721 90.H8.sp6:130950.Seq M00003761D:A09 722 17076 90.A9.sp6:130867.Seq M00003762C:B08 723 3108 90.B9.sp6:130879.Seq M00003763A:F06 724 67907 90.C9.sp6:130891.Seq M00003774C:A03 725 90.D9.sp6:130903.Seq M00003784D:D12 726 11350 90.F9.sp6:130927.Seq M00003826B:A06 727 7899 90.H9.sp6:130951.Seq M00003837D:A01 728 7798 90.A10.sp6:130868.Seq M00003839A:D08 729 6539 90.B10.sp6:130880.Seq M00003844C:B11 730 6874 90.C10.sp6:130892.Seq M00003846B:D06 731 90.D10.sp6:130904.Seq M00003851B:D08 732 13595 90.E10.sp6:130916.Seq M00003851B:D10 733 5619 90.F10.sp6:130928.Seq M00003853A:D04 734 10515 90.G10.sp6:130940.Seq M00003853A:F12 735 4622 90.H10.sp6:130952.Seq M00003856B:C02 736 3389 90.A11.sp6:130869.Seq M00003857A:G10 737 4718 90.B11.sp6:130881.Seq M00003857A:H03 738 90.C11.sp6:130893.Seq M00003867A:D10 739 12977 90.F11.sp6:130929.Seq M00003875B:F04 740 8479 90.G11.sp6:130941.Seq M00003875C:G07 741 90.H11.sp6:130953.Seq M00003875D:D11 742 7798 90.A12.sp6:130870.Seq M00003876D:E12 743 5345 90.B12.sp6:130882.Seq M00003879B:C11 744 31587 90.C12.sp6:130894.Seq M00003879B:D10 745 14507 90.D12.sp6:130906.Seq M00003879D:A02 746 13576 90.F12.sp6:130930.Seq M00003885C:A02 747 90.G12.sp6:130942.Seq M00003891C:H09 748 9285 90.H12.sp6:130954.Seq M00003906C:E10 749 39809 99.A1.sp6:131230.Seq M00003907D:A09 750 16317 99.B1.sp6:131242.Seq M00003907D:H04 751 8672 99.C1.sp6:131254.Seq M00003909D:C03 752 12532 99.D1.sp6:131266.Seq M00003912B:D01 753 3900 99.E1.sp6:131278.Seq M00003914C:F05 754 23255 99.F1.sp6:131290.Seq M00003922A:E06 755 24488 99.C2.sp6:131255.Seq M00003968B:F06 756 40122 99.D2.sp6:131267.Seq M00003970C:B09 757 23210 99.E2.sp6:131279.Seq M00003974D:E07 758 23358 99.F2.sp6:131291.Seq M00003974D:H02 759 3430 99.A3.sp6:131232.Seq M00003981A:E10 760 2433 99.B3.sp6:131244.Seq M00003982C:C02 761 9105 99.C3.sp6:131256.Seq M00003983A:A05 762 6124 99.D3.sp6:131268.Seq M00004028D:A06 763 40073 99.E3.sp6:131280.Seq M00004028D:C05 764 37285 99.H3.sp6:131316.Seq M00004035C:A07 765 17036 99.A4.sp6:131233.Seq M00004035D:B06 766 3706 99.C4.sp6:131257.Seq M00004068B:A01 767 99.D4.sp6:131269.Seq M00004072A:C03 768 15069 99.F4.sp6:131293.Seq M00004081C:D10 769 9285 99.H4.sp6:131317.Seq M00004086D:G06 770 6880 99.A5.sp6:131234.Seq M00004087D:A01 771 5325 99.C5.sp6:131258.Seq M00004093D:B12 772 7221 99.D5.sp6:131270.Seq M00004105C:A04 773 4937 99.E5.sp6:131282.Seq M00004108A:E06 774 6874 99.F5.sp6:131294.Seq M00004111D:A08 775 13183 99.G5.sp6:131306.Seq M00004114C:F11 776 99.H5.sp6:131318.Seq M00004121B:G01 777 13272 99.A6.sp6:131235.Seq M00004138B:H02 778 5257 99.B6.sp6:131247.Seq M00004146C:C11 779 6455 99.D6.sp6:131271.Seq M00004157C:A09 780 5319 99.E6.sp6:131283.Seq M00004169C:C12 781 4908 99.F6.sp6:131295.Seq M00004171D:B03 782 11494 99.G6.sp6:131307.Seq M00004172C:D08 783 11443 99.A7.sp6:131236.Seq M00004185C:C03 784 99.B7.sp6:131248.Seq M00004191D:B11 785 8210 99.C7.sp6:131260.Seq M00004197D:H01 786 14311 99.D7.sp6:131272.Seq M00004203B:C12 787 99.E7.sp6:131284.Seq M00004205D:F06 788 12971 99.B8.sp6:131249.Seq M00004223D:E04 789 6455 99.C8.sp6:131261.Seq M00004229B:F08 790 7212 99.D8.sp6:131273.Seq M00004230B:C07 791 4905 99.H8.sp6:131321.Seq M00004269D:D06 792 16914 99.A9.sp6:131238.Seq M00004275C:C11 793 16921 99.D9.sp6:131274.Seq M00004295D:F12 794 13046 99.E9.sp6:131286.Seq M00004296C:H07 795 9457 99.F9.sp6:131298.Seq M00004307C:A06 796 26295 99.G9.sp6:131310.Seq M00004312A:G03 797 21847 99.H9.sp6:131322.Seq M00004318C:D10 798 99.H10.sp6:131323.Seq M00004505D:F08 799 99.B11.sp6:131252.Seq M00004692A:H08 800 99.D11.sp6:131276.Seq M00005180C:G03 801 39304 RTA00000118A.j.21.1.Seq_THC151859 802 2428 RTA00000123A.1.21.1.Seq_THC205063 803 1058 RTA00000126A.e.20.3.Seq_THC217534 804 5097 RTA00000134A.k.1.1.Seq_THC215869 805 20212 RTA00000134A.1.22.1.Seq_THC128232 806 23255 RTA00000177AF.e.14.3.Seq_THC228776 807 2790 RTA00000177AF.e.2.1.Seq_THC229461 808 6420 RTA00000177AF.f.10.3.Seq_THC226443 809 4059 RTA00000177AF.n.18.3.Seq_THC123051 810 RTA00000179AF.j.13.1.Seq_THC105720 811 9952 RTA00000180AF.c.20.1.Seq_THC162284 812 13238 RTA00000181AF.m.4.1.Seq_THC140691 813 9685 RTA00000183AF.c.11.1.Seq_THC109544 814 RTA00000183AF.c.24.1.Seq_THC125912 815 6420 RTA00000183AF.d.11.1.Seq_THC226443 816 6974 RTA00000183AF.d.9.1.Seq_THC223129 817 40044 RTA00000183AF.g.22.1.Seq_THC232899 818 RTA00000183AF.g.9.1.Seq_THC198280 819 5892 RTA00000184AF.d.11.1.Seq_THC161896 820 40044 RTA00000186AF.d.1.1.Seq_THC232899 821 RTA00000186AF.h.14.1.Seq_THC112525 822 19267 RTA00000186AF.1.12.1.Seq_THC178183 823 8773 RTA00000187AF.f.24.1.Seq_THC220002 824 7570 RTA00000187AF.g.24.1.Seq_THC168636 825 11476 RTA00000187AF.p.19.1.Seq_THC108482 826 RTA00000188AF.d.11.1.Seq_THC212094 827 17076 RTA00000188AF.d.21.1.Seq_THC208760 828 697 RTA00000188AF.d.6.1.Seq_THC178884 829 67907 RTA00000188AF.g.11.1.Seq_THC123222 830 5619 RTA00000188AF.1.9.1.Seq_THC167845 831 4718 RTA00000189AF.g.5.1.Seq_THC196102 832 39809 RTA00000190AF.e.3.1.Seq_THC150217 833 23255 RTA00000190AF.j.4.1.Seq_THC228776 834 40122 RTA00000190AF.n.23.1.Seq_THC109227 835 23210 RTA00000190AF.o.20.1.Seq_THC207240 836 23358 RTA00000190AF.o.21.1.Seq_THC207240 837 5693 RTA00000190AF.p.17.2.Seq_THC173318 838 2433 RTA00000191AF.a.15.2.Seq_THC79498 839 5257 RTA00000192AF.f.3.1.Seq_THC213833 840 16392 RTA00000192AF.l.1.1.Seq_THC202071 841 RTA00000193AF.c.21.1.Seq_THC222602 842 26295 RTA00000193AF.i.24.2.Seq_THC197345 843 RTA00000193AF.m.5.1.Seq_THC173318 844 RTA00000193AF.n.15.1.Seq_THC215687

Example 2 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS:1-404, as well as the validation sequences SEQ ID NOS:405-800, were translated in all three reading frames to determine the best alignment with the individual sequences. These amino acid sequences and nucleotide sequences are referred, generally, as query sequences, which are aligned with the individual sequences. Query and individual sequences were aligned using the BLAST programs, available over the world wide web sit of the NCBI. Again the sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above in Example 1.

Table 2 (inserted before the claims) shows the results of the alignments. Table 2 refers to each sequence by its SEQ ID NO:, the accession numbers and descriptions of nearest neighbors from the Genbank and Non-Redundant Protein searches, and the p values of the search results. Table 1 identifies each SEQ ID NO: by SEQ name, clone ID, and cluster. As discussed above, a single cluster includes polynucleotides representing the same gene or gene family, and generally represents sequences encoding the same gene product.

For each of SEQ ID NOS:1-800, the best alignment to a protein or DNA sequence is included in Table 2. The activity of the polypeptide encoded by SEQ ID NOS:1-800 is the same or similar to the nearest neighbor reported in Table 2. The accession number of the nearest neighbor is reported, providing a reference to the activities exhibited by the nearest neighbor. The search program and database used for the alignment also are indicated as well as a calculation of the p value.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of SEQ ID NOS:1-800. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of SEQ ID NOS:1-800.

SEQ ID NOS:1-800 and the translations thereof may be human homologs of known genes of other species or novel allelic variants of known human genes. In such cases, these new human sequences are suitable as diagnostics or therapeutics. As diagnostics, the human sequences SEQ ID NOS:1-800 exhibit greater specificity in detecting and differentiating human cell lines and types than homologs of other species. The human polypeptides encoded by SEQ ID NOS:1-800 are likely to be less immunogenic when administered to humans than homologs from other species. Further, on administration to humans, the polypeptides encoded by SEQ ID NOS:1-800 can show greater specificity or can be better regulated by other human proteins than are homologs from other species.

Example 3 Members of Protein Families

After conducting a profile search as described in the specification above, several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 3). Thus the invention encompasses fragments, fusions, and variants of such polynucleotides that retain biological activity associated with the protein family and/or functional domain identified herein.

TABLE 3 Polynucleotides encoding gene products of a protein family or having a known functional domain(s). SEQ ID NO: Biological Activity (Profile hit) Start Stop Dir 24 4 transmembrane segments integral membrane proteins 1218 578 rev 41 4 transmembrane segments integral membrane proteins 1086 413 rev 101 4 transmembrane segments integral membrane proteins 1206 544 rev 157 4 transmembrane segments integral membrane proteins 721 33 rev 341 4 transmembrane segments integral membrane proteins 1253 613 rev 395 4 transmembrane segments integral membrane proteins 530 10 for 395 4 transmembrane segments integral membrane proteins 696 17 for 395 4 transmembrane segments integral membrane proteins 471 39 rev 24 7 transmembrane receptor (Secretin family) 1301 491 rev 41 7 transmembrane receptor (Secretin family) 1309 10 rev 101 7 transmembrane receptor (Secretin family) 1330 296 rev 157 7 transmembrane receptor (Secretin family) 1173 249 rev 291 7 transmembrane receptor (Secretin family) 1400 269 rev 291 7 transmembrane receptor (Secretin family) 712 130 for 305 7 transmembrane receptor (Secretin family) 926 4 for 305 7 transmembrane receptor (Secretin family) 753 55 rev 315 7 transmembrane receptor (Secretin family) 1058 270 rev 341 7 transmembrane receptor (Secretin family) 1265 534 rev 116 Ank repeat 141 218 for 251 Ank repeat 290 207 for 251 Ank repeat 467 387 for 63 ATPases Associated with Various Cellular Activities 543 60 for 116 ATPases Associated with Various Cellular Activities 802 313 for 134 ATPases Associated with Various Cellular Activities 525 57 rev 136 ATPases Associated with Various Cellular Activities 712 163 for 151 ATPases Associated with Various Cellular Activities 719 73 for 151 ATPases Associated with Various Cellular Activities 386 13 for 384 ATPases Associated with Various Cellular Activities 664 140 for 404 ATPases Associated with Various Cellular Activities 704 52 for 374 Basic region plus leucine zipper transcription factors 298 146 for 97 Bromodomain (conserved sequence found in human, 230 63 for Drosophila and yeast proteins.) 136 EF-hand 121 207 for 242 EF-hand 238 155 for 379 EF-hand 212 126 for 308 Eukaryotic aspartyl proteases 1300 461 rev 213 GATA family of transcription factors 720 377 for 367 G-protein alpha subunit 971 467 rev 188 Phorbol esters/diacylglycerol binding 91 177 for 251 Phorbol esters/diacylglycerol binding 133 219 for 202 protein kinase 482 1 rev 202 protein kinase 970 1 rev 315 protein kinase 739 158 for 315 protein kinase 1023 197 for 367 protein kinase 1046 285 rev 397 protein kinase 511 6 for 256 Protein phosphatase 2C 13 90 for 256 Protein phosphatase 2C 163 86 for 382 Protein Tyrosine Phosphatase 261 2 for 306 SH3 Domain 141 296 for 386 SH3 Domain 359 209 for 169 Trypsin 764 164 rev 188 WD domain, G-beta repeats 480 382 for 188 WD domain, G-beta repeats 206 117 for 335 WD domain, G-beta repeats 3 92 for 23 wnt family of developmental signaling proteins 1151 335 rev 291 wnt family of developmental signaling proteins 779 89 rev 291 wnt family of developmental signaling proteins 1347 382 rev 324 wnt family of developmental signaling proteins 1180 499 rev 330 wnt family of developmental signaling proteins 1180 499 rev 341 wnt family of developmental signaling proteins 1399 560 rev 353 wnt family of developmental signaling proteins 880 49 rev 188 WW/rsp5/WWP domain containing proteins 431 354 for 379 WW/rsp5/WWP domain containing proteins 12 89 for 395 WW/rsp5/WWP domain containing proteins 153 76 for 395 WW/rsp5/WWP domain containing proteins 156 64 for 61 Zinc finger, C2H2 type 254 192 for 306 Zinc finger, C2H2 type 428 367 for 386 Zinc finger, C2H2 type 191 253 for 322 Zinc finger, CCHC class 553 503 for 306 Zinc-binding metalloprotease domain 101 60 rev 395 Zinc-binding metalloprotease domain 28 69 rev

Start and stop indicate the position within the individual sequences that align with the query sequence having the indicated SEQ ID NO. The direction (Dir) indicates the orientation of the query sequence with respect to the individual sequence, where forward (for) indicates that the alignment is in the same direction (left to right) as the sequence provided in the Sequence Listing and reverse (rev) indicates that the alignment is with a sequence complementary to the sequence provided in the Sequence Listing. Some polynucleotides exhibited multiple profile hits because, for example, the particular sequence contains overlapping profile regions, and/or the sequence contains two different functional domains. These profile hits are described in more detail below.

a) Four Transmembrane Integral Membrane Proteins. SEQ ID NOS: 24, 41, 101, 157, 341, and 395 correspond to a sequence encoding a polypeptide that is a member of the 4 transmembrane segments integral membrane protein family (transmembrane 4 family). The transmembrane 4 family of proteins includes a number of evolutionarily-related eukaryotic cell surface antigens (Levy et al., J. Biol. Chem., (1991) 266:14597; Tomlinson et al., Eur. J. Immunol. (1993) 23:136; Barclay et al. The leucocyte antigen factbooks. (1993) Academic Press, London/San Diego). The proteins belonging to this family include: 1) Mammalian antigen CD9 (MIC3), which is involved in platelet activation and aggregation; 2) Mammalian leukocyte antigen CD37, expressed on B lymphocytes; 3) Mammalian leukocyte antigen CD53 (OX-44), which is implicated in growth regulation in hematopoietic cells; 4) Mammalian lysosomal membrane protein CD63 (melanoma-associated antigen ME491; antigen AD1); 5) Mammalian antigen CD81 (cell surface protein TAPA-1), which is implicated in regulation of lymphoma cell growth; 6) Mammalian antigen CD82 (protein R2; antigen C33; Kangai 1 (KAI1)), which associates with CD4 or CD8 and delivers costimulatory signals for the TCR/CD3 pathway; 7) Mammalian antigen CD151 (SFA-1; platelet-endothelial tetraspan antigen 3 (PETA-3)); 8) Mammalian cell surface glycoprotein A15 (TALLA-1; MXS1); 9) Mammalian novel antigen 2 (NAG-2); 10) Human tumor-associated antigen CO-029; 11) Schistosoma mansoni and japonicum 23 Kd surface antigen (SM23/SJ23).

The members of the 4 transmembrane family share several characteristics. First, they all are apparently type III membrane proteins, which are integral membrane proteins containing an N-terminal membrane-anchoring domain which is not cleaved during biosynthesis and which functions both as a translocation signal and as a membrane anchor. The family members also contain three additional transmembrane regions, at least seven conserved cysteines residues, and are of approximately the same size (218 to 284 residues). These proteins are collectively know as the “transmembrane 4 superfamily” (TM4) because they span plasma membrane four times. A schematic diagram of the domain structure of these proteins is as follows:

where Cyt is the cytoplasmic domain, TMa is the transmembrane anchor; TM2 to TM4 represents transmembrane regions 2 to 4, ‘C’ are conserved cysteines, and ‘*’ indicates the position of the consensus pattern. The consensus pattern spans a conserved region including two cysteines located in a short cytoplasmic loop between two transmembrane domains: Consensus pattern: G-x(3)-[LIVMF]-x(2)-[GSA]-[LIVMF](2)-G-C-x-[GA]-[STA]-x(2)-[EG]-x(2)-[CWN]-[LIVM](2).

b) Seven Transmembrane Integral Membrane Proteins. SEQ ID NOS: 24, 41, 101, 157, 291, 305, 315, and 341 correspond to a sequence encoding a polypeptide that is a member of the seven transmembrane receptor family. G-protein coupled receptors (Strosberg, Eur. J. Biochem. (1991) 196:1; Kerlavage, Curr. Opin. Struct. Biol. (1991) 1:394; and Probst et al., DNA Cell Biol. (1992) 11:1; and Savarese et al., Biochem. J. (1992) 293:1) (also called R7G) are an extensive group of hormones, neurotransmitters, odorants and light receptors which transduce extracellular signals by interaction with guanine nucleotide-binding (G) proteins. The tertiary structure of these receptors is thought to be highly similar. They have seven hydrophobic regions, each of which most probably spans the membrane. The N-terminus is located on the extracellular side of the membrane and is often glycosylated, while the C-terminus is cytoplasmic and generally phosphorylated. Three extracellular loops alternate with three intracellular loops to link the seven transmembrane regions. Most, but not all of these receptors, lack a signal peptide. The most conserved parts of these proteins are the transmembrane regions and the first two cytoplasmic loops. A conserved acidic-Arg-aromatic triplet is present in the N-terminal extremity of the second cytoplasmic loop (Attwood et al., Gene (1991) 98:153) and could be implicated in the interaction with G proteins.

To detect this widespread family of proteins a pattern is used that contains the conserved triplet and that also spans the major part of the third transmembrane helix. Additional information about the seven transmembrane receptor family, and methods for their identification and use, is found in U.S. Pat. No. 5,759,804. Due in part to their expression on the cell surface and other attractive characteristics, seven transmembrane protein family members are of particular interest as drug targets, as surface antigen markers, and as drug delivery targets (e.g., using antibody-drug complexes and/or use of anti-seven transmembrane protein antibodies as therapeutics in their own right).

c) Ank Repeats. SEQ ID NOS: 116 and 251 represent polynucleotides encoding Ank repeat-containing proteins. The ankyrin motif is a 33 amino acid sequence named after the protein ankyrin which has 24 tandem 33-amino-acid motifs. Ank repeats were originally identified in the cell-cycle-control protein cdc10 (Breeden et al., Nature (1987) 329:651). Proteins containing ankyrin repeats include ankyrin, myotropin, I-kappaB proteins, cell cycle protein cdc10, the Notch receptor (Matsuno et al., Development (1997) 124(21):4265); G9a (or BAT8) of the class III region of the major histocompatibility complex (Biochem J. 290:811-818, 1993), FABP, GABP, 53BP2, Lin12, glp-1, SW14, and SW16. The functions of the ankyrin repeats are compatible with a role in protein-protein interactions (Bork, Proteins (1993) 17(4):363; Lambert and Bennet, Eur. J. Biochem. (1993) 211:1; Kerr et al., Current Op. Cell Biol. (1992) 4:496; Bennet et al., J. Biol. Chem. (1980) 255:6424).

The 90 kD N-terminal domain of ankyrin contains a series of 24 33-amino-acid ank repeats. (Lux et al., Nature (1990) 344:36-42, Lambert et al., PNAS USA (1990) 87:1730.) The 24 ank repeats form four folded subdomains of 6 repeats each. These four repeat subdomains mediate interactions with at least 7 different families of membrane proteins. Ankyrin contains two separate binding sites for anion exchanger dimers. One site utilizes repeat subdomain two (repeats 7-12) and the other requires both repeat subdomains 3 and 4 (repeats 13-24). Since the anion exchangers exist in dimers, ankyrin binds 4 anion exchangers at the same time. (Michaely and Bennett, J. Biol. Chem. (1995) 270(37):22050) The repeat motifs are involved in ankyrin interaction with tubulin, spectrin, and other membrane proteins. (Lux et al., Nature (1990) 344:36.)

The Rel/NF-kappaB/Dorsal family of transcription factors have activity that is controlled by sequestration in the cytoplasm in association with inhibitory proteins referred to as I-kappaB. (Gilmore, Cell (1990) 62:841; Nolan and Baltimore, Curr Opin Genet Dev. (1992) 2:211; Baeuerle, Biochim Biophys Acta (1991) 1072:63; Schmitz et al., Trends Cell Biol. (1991) 1:130.) I-kappaB proteins contain 5 to 8 copies of 33 amino acid ankyrin repeats and certain NF-kappaB/rel proteins are also regulated by cis-acting ankyrin repeat containing domains including p105NF-kappaB which contains a series of ankyrin repeats (Diehl and Hannink, J. Virol. (1993) 67(12):7161). The I-kappaBs and Cactus (also containing ankyrin repeats) inhibit activators through differential interactions with the Rel-homology domain. The gene family includes proto-oncogenes, thus broadly implicating I-kappaB in the control of both normal gene expression and the aberrant gene expression that makes cells cancerous. (Nolan and Baltimore, Curr Opin Genet Dev. (1992) 2(2):211-220). In the case of rel/NF-kappaB and pp40/I-kappaBβ, both the ankyrin repeats and the carboxy-terminal domain are required for inhibiting DNA-binding activity and direct association of pp40/I-kappaBβ with rel/NF-kappaB protein. The ankyrin repeats and the carboxy-terminal of pp40/I-kappaBβ (form a structure that associates with the rel homology domain to inhibit DNA binding activity (Inoue et al., PNAS USA (1992) 89:4333).

The 4 ankyrin repeats in the amino terminus of the transcription factor subunit GABPβ are required for its interaction with the GABPα subunit to form a functional high affinity DNA-binding protein. These repeats can be crosslinked to DNA when GABP is bound to its target sequence. (Thompson et al., Science (1991) 253:762; LaMarco et al., Science (1991) 253:789).

Myotrophin, a 12.5 kDa protein having a key role in the initiation of cardiac hypertrophy, comprises ankyrin repeats. The ankyrin repeats are characteristic of a hairpin-like protruding tip followed by a helix-turn-helix motif. The V-shaped helix-turn-helix of the repeats stack sequentially in bundles and are stabilized by compact hydrophobic cores, whereas the protruding tips are less ordered.

d) ATPases Associated with Various Cellular Activities (AAA). SEQ ID NOS: 63, 116, 134, 136, 151, 384, and 404 polynucleotides encoding novel members of the “ATPases Associated with diverse cellular Activities” (AAA) protein family The AAA protein family is composed of a large number of ATPases that share a conserved region of about 220 amino acids that contains an ATP-binding site (Froehlich et al., J. Cell Biol. (1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieri et al., BioEssays (1995) 17:639; see internet site at yeamob.pci.chemie.uni-tuebingen.de/A-AA/Description.html). The proteins that belong to this family either contain one or two AAA domains.

Proteins containing two AAA domains include: 1) Mammalian and drosophila NSF (N-ethylmaleimide-sensitive fusion protein) and the fungal homolog, SEC18, which are involved in intracellular transport between the endoplasmic reticulum and Golgi, as well as between different Golgi cisternae; 2) Mammalian transitional endoplasmic reticulum ATPase (previously known as p97 or VCP), which is involved in the transfer of membranes from the endoplasmic reticulum to the golgi apparatus. This ATPase forms a ring-shaped homooligomer composed of six subunits. The yeast homolog, CDC48, plays a role in spindle pole proliferation; 3) Yeast protein PAS1 essential for peroxisome assembly and the related protein PAS1 from Pichia pastoris; 4) Yeast protein AFG2; 5) Sulfolobus acidocaldarius protein SAV and Halobacterium salinarium cdcH; which may be part of a transduction pathway connecting light to cell division.

Proteins containing a single AAA domain include: 1) Escherichia coli and other bacteria ftsH (or hflB) protein. FtsH is an ATP-dependent zinc metallopeptidase that degrades the heat-shock sigma-32 factor, and is an integral membrane protein with a large cytoplasmic C-terminal domain that contain both the AAA and the protease domains; 2) Yeast protein YME1, a protein important for maintaining the integrity of the mitochondrial compartment. YME1 is also a zinc-dependent protease; 3) Yeast protein AFG3 (or YTA10). This protein also contains an AAA domain followed by a zinc-dependent protease domain; 4) Subunits from regulatory complex of the 26S proteasome (Hilt et al., Trends Biochem. Sci. (1996) 21:96), which is involved in the ATP-dependent degradation of ubiquitinated proteins, which subunits include: a) Mammalian 4 and homologs in other higher eukaryotes, in yeast (gene YTA5) and fission yeast (gene mts2); b) Mammalian 6 (TBP7) and homologs in other higher eukaryotes and in yeast (gene YTA2); c) Mammalian subunit 7 (MSS1) and homologs in other higher eukaryotes and in yeast (gene CIM5 or YTA3); d) Mammalian subunit 8 (P45) and homologs in other higher eukaryotes and in yeast (SUG1 or CIM3 or TBY1) and fission yeast (gene let1); e) Other probable subunits include human TBP1, which influences HIV gene expression by interacting with the virus tat transactivator protein, and yeast YTA1 and YTA6; 5) Yeast protein BCS1, a mitochondrial protein essential for the expression of the Rieske iron-sulfur protein; 6) Yeast protein MSP1, a protein involved in intramitochondrial sorting of proteins; 7) Yeast protein PAS8, and the corresponding proteins PAS5 from Pichia pastoris and PAY4 from Yarrowia lipolytica; 8) Mouse protein SKD1 and its fission yeast homolog (SpAC2G11.06); 9) Caenorhabditis elegans meiotic spindle formation protein mei-1; 10) Yeast protein SAP1′ 11) Yeast protein YTA7; and 12) Mycobacterium leprae hypothetical protein A2126A.

In general, the AAA domains in these proteins act as ATP-dependent protein clamps (Confalonieri et al. (1995) BioEssays 17:639). In addition to the ATP-binding ‘A’ and ‘B’ motifs, which are located in the N-terminal half of this domain, there is a highly conserved region located in the central part of the domain which was used in the development of the signature pattern.

e) Basic Region Plus Leucine Zipper Transcription Factors. SEQ ID NO:374 correspond to a polynucleotide encoding a novel member of the family of basic region plus leucine zipper transcription factors. The bZIP superfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcription factors encompasses proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper required for dimerization. Members of the family include transcription factor AP-1, which binds selectively to enhancer elements in the cis control regions of SV40 and metallothionein IIA. AP-1, also known as c-jun, is the cellular homolog of the avian sarcoma virus 17 (ASV17) oncogene v-jun.

Other members of this protein family include jun-B and jun-D, probable transcription factors that are highly similar to jun/AP-1; the fos protein, a proto-oncogene that forms a non-covalent dimer with c-jun; the fos-related proteins fra-1, and fos B; and mammalian cAMP response element (CRE) binding proteins CREB, CREM, ATF-1, ATF-3, ATF-4, ATF-5, ATF-6 and LRF-1.

f) Bromodomain. SEQ ID NO:97 corresponds to a polynucleotide encoding a polypeptide having a bromodomain region (Haynes et al., 1992, Nucleic Acids Res. 20:2693-2603, Tamkun et al., 1992, Cell 68:561-572, and Tamkun, 1995, Curr. Opin. Genet. Dev. 5:473-477), which is a conserved region of about 70 amino acids found in the following proteins: 1) Higher eukaryotes transcription initiation factor TFIID 250 Kd subunit (TBP-associated factor p250) (gene CCG1); P250 is associated with the TFIID TATA-box binding protein and seems essential for progression of the G1 phase of the cell cycle. 2) Human RING3, a protein of unknown function encoded in the MHC class II locus; 3) Mammalian CREB-binding protein (CBP), which mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein; 4) Mammalian homologs of brahma, including three brahma-like human: SNF2a(hBRM), SNF2b, and BRG1; 5) Human BS69, a protein that binds to adenovirus E1A and inhibits E1A transactivation; 6) Human peregrin (or Br140).

The bromodomain is thought to be involved in protein-protein interactions and may be important for the assembly or activity of multicomponent complexes involved in transcriptional activation.

g) EF-Hand. SEQ ID NOS:136, 242, and 379 correspond to polynucleotides encoding a novel protein in the family of EF-hand proteins. Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand (Kawasaki et al., Protein. Prof. (1995) 2:305-490). This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).

Proteins known to contain EF-hand regions include: Calmodulin (Ca=4, except in yeast where Ca=3) (“Ca=” indicates approximate number of EF-hand regions); diacylglycerol kinase (EC 2.7.1.107) (DGK) (Ca=2); 2) FAD-dependent glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) from mammals (Ca=1); guanylate cyclase activating protein (GCAP) (Ca=3); MIF related proteins 8 (MRP-8 or CFAG) and 14 (MRP-14) (Ca=2); myosin regulatory light chains (Ca=1); oncomodulin (Ca=2); osteonectin (basement membrane protein BM-40) (SPARC); and proteins that contain an “osteonectin” domain (QR1, matrix glycoprotein SC1).

The consensus pattern includes the complete EF-hand loop as well as the first residue which follows the loop and which seem to always be hydrophobic.

h) Eukaryotic Aspartyl Proteases. SEQ ID NO:308 corresponds to a gene encoding a novel eukaryotic aspartyl protease. Aspartyl proteases, known as acid proteases, (EC 3.4.23.-) are a widely distributed family of proteolytic enzymes (Foltmann B., Essays Biochem. (1981) 17:52; Davies D. R., Annu. Rev. Biophys. Chem. (1990) 19:189; Rao J. K. M., et al., Biochemistry (1991) 30:4663) known to exist in vertebrates, fungi, plants, retroviruses and some plant viruses. Aspartate proteases of eukaryotes are monomeric enzymes which consist of two domains. Each domain contains an active site centered on a catalytic aspartyl residue. The two domains most probably evolved from the duplication of an ancestral gene encoding a primordial domain. Currently known eukaryotic aspartyl proteases include: 1) Vertebrate gastric pepsins A and C (also known as gastricsin); 2) Vertebrate chymosin (rennin), involved in digestion and used for making cheese; 3) Vertebrate lysosomal cathepsins D (EC 3.4.23.5) and E (EC 3.4.23.34); 4) Mammalian renin (EC 3.4.23.15) whose function is to generate angiotensin I from angiotensinogen in the plasma; 5) Fungal proteases such as aspergillopepsin A (EC 3.4.23.18), candidapepsin (EC 3.4.23.24), mucoropepsin (EC 3.4.23.23) (mucor rennin), endothiapepsin (EC 3.4.23.22), polyporopepsin (EC 3.4.23.29), and rhizopuspepsin (EC 3.4.23.21); and 6) Yeast saccharopepsin (EC 3.4.23.25) (proteinase A) (gene PEP4). PEP4 is implicated in posttranslational regulation of vacuolar hydrolases; 7) Yeast barrierpepsin (EC 3.4.23.35) (gene BAR1); a protease that cleaves alpha-factor and thus acts as an antagonist of the mating pheromone; and 8) Fission yeast sxa1 which is involved in degrading or processing the mating pheromones.

Most retroviruses and some plant viruses, such as badnaviruses, encode for an aspartyl protease which is an homodimer of a chain of about 95 to 125 amino acids. In most retroviruses, the protease is encoded as a segment of a polyprotein which is cleaved during the maturation process of the virus. It is generally part of the pol polyprotein and, more rarely, of the gag polyprotein. Because the sequence around the two aspartates of eukaryotic aspartyl proteases and around the single active site of the viral proteases is conserved, a single signature pattern can be used to identify members of both groups of proteases.

i) GATA Family of Transcription Factors. SEQ ID NO:213 corresponds to a novel member of the GATA family of transcription factors. The GATA family of transcription factors are proteins that bind to DNA sites with the consensus sequence (A/T)GATA(A/G), found within the regulatory region of a number of genes. Proteins currently known to belong to this family are: 1) GATA-1 (Trainor, C. D., et al., Nature (1990) 343:92) (also known as Eryf1, GF-1 or NF-E1), which binds to the GATA region of globin genes and other genes expressed in erythroid cells. It is a transcriptional activator which probably serves as a general ‘switch’ factor for erythroid development; 2) GATA-2 (Lee, M. E., et al., J. Biol. Chem. (1991) 266:16188), a transcriptional activator which regulates endothelin-1 gene expression in endothelial cells; 3) GATA-3 (Ho, I.-C., et al., EMBO J. (1991) 10:1187), a transcriptional activator which binds to the enhancer of the T-cell receptor alpha and delta genes; 4) GATA-4 (Spieth, J., et al., Mol. Cell. Biol. (1991) 11:4651), a transcriptional activator expressed in endodermally derived tissues and heart; 5) Drosophila protein pannier (or DGATAa) (gene pnr) which acts as a repressor of the achaete-scute complex (as-c); 6) Bombyx mori BCFI (Drevet, J. R., et al., J. Biol. Chem. (1994) 269:10660), which regulates the expression of chorion genes; 7) Caenorhabditis elegans elt-1 and elt-2, transcriptional activators of genes containing the GATA region, including vitellogenin genes (Hawkins, M. G., et al., J. Biol. Chem. (1995) 270:14666); 8) Ustilago maydis urbs1 (Voisard, C. P. O., et al., Mol. Cell. Biol. (1993) 13:7091), a protein involved in the repression of the biosynthesis of siderophores; 9) Fission yeast protein GAF2.

All these transcription factors contain a pair of highly similar ‘zinc finger’ type domains with the consensus sequence C-x2-C-x17-C-x2-C. Some other proteins contain a single zinc finger motif highly related to those of the GATA transcription factors. These proteins are: 1) Drosophila box A-binding factor (ABF) (also known as protein serpent (gene srp)) which may function as a transcriptional activator protein and may play a key role in the organogenesis of the fat body; 2) Emericella nidulans are (Arst, H. N., Jr., et al., Trends Genet. (1989) 5:291) a transcriptional activator which mediates nitrogen metabolite repression; 3) Neurospora crassa nit-2 (Fu, Y.-H., et al., Mol. Cell. Biol. (1990) 10:1056), a transcriptional activator which turns on the expression of genes coding for enzymes required for the use of a variety of secondary nitrogen sources, during conditions of nitrogen limitation; 4) Neurospora crassa white collar proteins 1 and 2 (WC-1 and WC-2), which control expression of light-regulated genes; 5) Saccharomyces cerevisiae DAL81 (or UGA43), a negative nitrogen regulatory protein; 6) Saccharomyces cerevisiae GLN3, a positive nitrogen regulatory protein; 7) Saccharomyces cerevisiae GAT1; 8) Saccharomyces cerevisiae GZF3.

j) G-Protein Alpha Subunit. SEQ ID NO:367 corresponds to a gene encoding a novel polypeptide of the G-protein alpha subunit family. Guanine nucleotide binding proteins (G-proteins) are a family of membrane-associated proteins that couple extracellularly-activated integral-membrane receptors to intracellular effectors, such as ion channels and enzymes that vary the concentration of second messenger molecules. G-proteins are composed of 3 subunits (alpha, beta and gamma) which, in the resting state, associate as a trimer at the inner face of the plasma membrane. The alpha subunit has a molecule of guanosine diphosphate (GDP) bound to it. Stimulation of the G-protein by an activated receptor leads to its exchange for GTP (guanosine triphosphate). This results in the separation of the alpha from the beta and gamma subunits, which always remain tightly associated as a dimer. Both the alpha and beta-gamma subunits are then able to interact with effectors, either individually or in a cooperative manner. The intrinsic GTPase activity of the alpha subunit hydrolyses the bound GTP to GDP. This returns the alpha subunit to its inactive conformation and allows it to reassociate with the beta-gamma subunit, thus restoring the system to its resting state.

G-protein alpha subunits are 350-400 amino acids in length and have molecular weights in the range 40-45 kDa. Seventeen distinct types of alpha subunit have been identified in mammals. These fall into 4 main groups on the basis of both sequence similarity and function: alpha-s, alpha-q, alpha-i and alpha-12 (Simon et al., Science (1993) 252:802). Many alpha subunits are substrates for ADP-ribosylation by cholera or pertussis toxins. They are often N-terminally acylated, usually with myristate and/or palmitoylate, and these fatty acid modifications are probably important for membrane association and high-affinity interactions with other proteins. The atomic structure of the alpha subunit of the G-protein involved in mammalian vision, transducin, has been elucidated in both GTP- and GDB-bound forms, and shows considerable similarity in both primary and tertiary structure in the nucleotide-binding regions to other guanine nucleotide binding proteins, such as p21-ras and EF-Tu.

k) Phorbol Esters/Diacylglycerol Binding. SEQ ID NO:188 and 251 represent polynucleotides encoding a protein belonging to the family including phorbol esters/diacylglycerol binding proteins. Diacylglycerol (DAG) is an important second messenger. Phorbol esters (PE) are analogues of DAG and potent tumor promoters that cause a variety of physiological changes when administered to both cells and tissues. DAG activates a family of serine/threonine protein kinases, collectively known as protein kinase C (PKC) (Azzi et al., Eur. J. Biochem. (1992) 208:547). Phorbol esters can directly stimulate PKC. The N-terminal region of PKC, known as C1, has been shown (Ono et al., Proc. Natl. Acad. Sci. USA (1989) 86:4868) to bind PE and DAG in a phospholipid and zinc-dependent fashion. The C1 region contains one or two copies (depending on the isozyme of PKC) of a cysteine-rich domain about 50 amino-acid residues long and essential for DAG/PE-binding. Such a domain has also been found in, for example, the following proteins.

(1) Diacylglycerol kinase (EC 2.7.1.107) (DGK) (Sakane et al., Nature (1990) 344:345), the enzyme that converts DAG into phosphatidate. It contains two copies of the DAG/PE-binding domain in its N-terminal section. At least five different forms of DGK are known in mammals; and

(2) N-chimaerin, a brain specific protein which shows sequence similarities with the BCR protein at its C-terminal part and contains a single copy of the DAG/PE-binding domain at its N-terminal part. It has been shown (Ahmed et al., Biochem. J. (1990) 272:767, and Ahmed et al., Biochem. J. (1991) 280:233) to be able to bind phorbol esters.

The DAG/PE-binding domain binds two zinc ions; the ligands of these metal ions are probably the six cysteines and two histidines that are conserved in this domain. The signature pattern completely spans the DAG/PE domain. The consensus pattern is: H-x-[LIVMFYW]-x(8,11)-C-x(2)-C-x(3)-[LIVMFC]-x(5,10)-C-x(2)-C-x(4)-[HD]-x(2)-C-x(5,9)-C. All the C and H are probably involved in binding zinc.

l) Protein Kinase. SEQ ID NOS:202, 315, 367, and 397 represent polynucleotides encoding protein kinases. Protein kinases catalyze phosphorylation of proteins in a variety of pathways, and are implicated in cancer. Eukaryotic protein kinases (Hanks S. K., et al., FASEB J. (1995) 9:576; Hunter T., Meth. Enzymol. (1991) 200:3; Hanks S. K., et al., Meth. Enzymol. (1991) 200:38; Hanks S. K., Curr. Opin. Struct. Biol. (1991) 1:369; Hanks S. K., et al., Science (1988) 241:42) are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. Two of the conserved regions are the basis for the signature pattern in the protein kinase profile. The first region, which is located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. The second region, which is located in the central part of the catalytic domain, contains a conserved aspartic acid residue which is important for the catalytic activity of the enzyme (Knighton D. R., et al., Science (1991) 253:407). The protein kinase profile includes two signature patterns for this second region: one specific for serine/threonine kinases and the other for tyrosine kinases. A third profile is based on the alignment in (Hanks S. K., et al., FASEB J. (1995) 9:576) and covers the entire catalytic domain.

The protein kinase profile also detects receptor guanylate cyclases and 2-5A-dependent ribonucleases. Sequence similarities between these two families and the eukaryotic protein kinase family have been noticed previously. The profile also detects Arabidopsis thaliana kinase-like protein TMKL1 which seems to have lost its catalytic activity.

If a protein analyzed includes the two of the above protein kinase signatures, the probability of it being a protein kinase is close to 100%. Eukaryotic-type protein kinases have also been found in prokaryotes such as Myxococcus xanthus (Munoz-Dorado J., et al, Cell (1991) 67:995) and Yersinia pseudotuberculosis. The patterns shown above has been updated since their publication in (Bairoch A., et al., Nature (1988) 331:22).

m) Protein Phosphatase 2C, SEQ ID NO:256 corresponds to a polynucleotide encoding a novel protein phosphatase 2C (PP2C), which is one of the four major classes of mammalian serine/threonine specific protein phosphatases. PP2C (Wenk et al., FEBS Lett. (1992) 297:135) is a monomeric enzyme of about 42 Kd which shows broad substrate specificity and is dependent on divalent cations (mainly manganese and magnesium) for its activity. Three isozymes are currently known in mammals: PP2C-alpha, -beta and -gamma.

n) Protein Tyrosine Phosphatase. SEQ ID NO:382 represents a polynucleotide encoding a protein tyrosine kinase. Tyrosine specific protein phosphatases (EC 3.1.3.48) (PTPase) (Fischer et al., Science (1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463; Trowbridge, J. Biol. Chem. (1991) 266:23517; Tonks et al., Trends Biochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013) catalyze the removal of a phosphate group attached to a tyrosine residue. These enzymes are very important in the control of cell growth, proliferation, differentiation and transformation. Multiple forms of PTPase have been characterized and can be classified into two categories: soluble PTPases and transmembrane receptor proteins that contain PTPase domain(s).

Soluble PTPases include PTPN3 (H1) and PTPN4 (MEG), enzymes that contain an N-terminal band 4.1-like domain and could act at junctions between the membrane and cytoskeleton; PTPN6 (PTP-1C; HCP; SHP) and PTPN11 (PTP-2C; SH-PTP3; Syp), enzymes that contain two copies of the SH2 domain at its N-terminal extremity.

Dual specificity PTPases include DUSP1 (PTPN10; MAP kinase phosphatase-1; MKP-1) which dephosphorylates MAP kinase on both Thr-183 and Tyr-185; and DUSP2 (PAC-1), a nuclear enzyme that dephosphorylates MAP kinases ERK1 and ERK2 on both Thr and Tyr residues.

Structurally, all known receptor PTPases are made up of a variable length extracellular domain, followed by a transmembrane region and a C-terminal catalytic cytoplasmic domain. Some of the receptor PTPases contain fibronectin type III (FN-III) repeats, immunoglobulin-like domains, MAM domains or carbonic anhydrase-like domains in their extracellular region. The cytoplasmic region generally contains two copies of the PTPAse domain. The first seems to have enzymatic activity, while the second is inactive but seems to affect substrate specificity of the first. In these domains, the catalytic cysteine is generally conserved but some other, presumably important, residues are not.

PTPase domains consist of about 300 amino acids. There are two conserved cysteines and the second one has been shown to be absolutely required for activity. Furthermore, a number of conserved residues in its immediate vicinity have also been shown to be important. The consensus pattern for PTPases is: [LIVMF]-H-C-x(2)-G-x(3)-[STC]-[STAGP]-x-[LIVMFY]; C is the active site residue.

o) SH3 Domain. SEQ ID NO:306 and 386 represent polynucleotides encoding SH3 domain proteins. The Src homology 3 (SH3) domain is a small protein domain of about 60 amino acid residues first identified as a conserved sequence in the non-catalytic part of several cytoplasmic protein tyrosine kinases (e.g. Src, Abl, Lck) (Mayer et al., Nature (1988) 332:272). The domain has also been found in a variety of intracellular or membrane-associated proteins (Musacchio et al., FEBS Lett. (1992) 307:55; Pawson et al., Curr. Biol. (1993) 3:434; Mayer et al., Trends Cell Biol. (1993) 3:8; and Pawson et al., Nature (1995) 373:573).

The SH3 domain has a characteristic fold that consists of five or six beta-strands arranged as two tightly packed anti-parallel beta sheets. The linker regions may contain short helices (Kuriyan et al., Curr. Opin. Struct. Biol. (1993) 3:828). It is believed that SH3 domain-containing proteins mediate assembly of specific protein complexes via binding to proline-rich peptides (Morton et al., Curr. Biol. (1994) 4:615). In general, SH3 domains are found as single copies in a given protein, but there is a significant number of proteins with two SH3 domains and a few with 3 or 4 copies.

SH3 domains have been identified in, for example, protein tyrosine kinases, such as the Src, Abl, Bkt, Csk and ZAP70 families of kinases; mammalian phosphatidylinositol-specific phospholipase C-gamma-1 and -2; mammalian phosphatidyl inositol 3-kinase regulatory p85 subunit; mammalian Ras GTPase-activating protein (GAP); mammalian Vav oncoprotein, a guanine nucleotide exchange factor of the CDC24 family; Drosophila lethal(1)discs large-1 tumor suppressor protein (gene Dlg1); mammalian tight junction protein ZO-1; vertebrate erythrocyte membrane protein p55; Caenorhabditis elegans protein lin-2; rat protein CASK; and mammalian synaptic proteins SAP90/PSD-95, CHAPSYN-110/PSD-93, SAP97/DLG1 and SAP102. Novel SH3-domain containing polypeptides will facilitate elucidation of the role of such proteins in important biological pathways, such as ras activation.

p) Trypsin. SEQ ID NO:169 corresponds to a novel serine protease of the trypsin family. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved in this family of proteases (Brenner S., Nature (1988) 334:528). Proteases known to belong to the trypsin family include: 1) Acrosin; 2) Blood coagulation factors VII, IX, X, XI and XII, thrombin, plasminogen, and protein C; 3) Cathepsin G; 4) Chymotrypsins; 5) Complement components C1r, C1s, C2, and complement factors B, D and I; 6) Complement-activating component of RA-reactive factor; 7) Cytotoxic cell proteases (granzymes A to H); 8) Duodenase I; 9) Elastases 1, 2, 3A, 3B (protease E), leukocyte (medullasin); 10) Enterokinase (EC 3.4.21.9) (enteropeptidase); 11) Hepatocyte growth factor activator; 12) Hepsin; 13) Glandular (tissue) kallikreins (including EGF-binding protein types A, B, and C, NGF-gamma chain, gamma-renin, prostate specific antigen (PSA) and tonin); 14) Plasma kallikrein; 15) Mast cell proteases (MCP) 1 (chymase) to 8; 16) Myeloblastin (proteinase 3) (Wegener's autoantigen); 17) Plasminogen activators (urokinase-type, and tissue-type); 18) Trypsins I, II, III, and IV; 19) Tryptases; 20) Snake venom proteases such as ancrod, batroxobin, cerastobin, flavoxobin, and protein C activator; 21) Collagenase from common cattle grub and collagenolytic protease from Atlantic sand fiddler crab; 22) Apolipoprotein(a); 23) Blood fluke cercarial protease; 24) Drosophila trypsin like proteases: alpha, easter, snake-locus; 25) Drosophila protease stubble (gene sb); and 26) Major mite fecal allergen Der p III. All the above proteins belong to family S1 in the classification of peptidases (Rawlings N. D., et al., Meth. Enzymol. (1994) 244:19; see worldwide web site at expasy.ch/cgi-bin/lists?peptidas.txt and originate from eukaryotic species. It should be noted that bacterial proteases that belong to family S2A are similar enough in the regions of the active site residues that they can be picked up by the same patterns.

q) WD Domain, G-Beta Repeats. SEQ ID NOS:188 and 335 represent novel members of the WD domain/G-beta repeat family. Beta-transducin (G-beta) is one of the three subunits (alpha, beta, and gamma) of the guanine nucleotide-binding proteins (G proteins) which act as intermediaries in the transduction of signals generated by transmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds to and hydrolyzes GTP; the functions of the beta and gamma subunits are less clear but they seem to be required for the replacement of GDP by GTP as well as for membrane anchoring and receptor recognition.

In higher eukaryotes, G-beta exists as a small multigene family of highly conserved proteins of about 340 amino acid residues. Structurally, G-beta consists of eight tandem repeats of about 40 residues, each containing a central Trp-Asp motif (this type of repeat is sometimes called a WD-40 repeat). Such a repetitive segment has been shown to exist in a number of other proteins including: human LIS1, a neuronal protein involved in type-1 lissencephaly; and mammalian coatomer beta′ subunit (beta′-COP), a component of a cytosolic protein complex that reversibly associates with Golgi membranes to form vesicles that mediate biosynthetic protein transport.

r) wnt Family of Developmental Signaling Proteins. SEQ ID NO: 23, 291, 324, 330, 341, and 353 correspond to novel members of the wnt family of developmental signaling proteins. Wnt-1 (previously known as int-1), the seminal member of this family, (Nusse R., Trends Genet. (1988) 4:291) is a proto-oncogene induced by the integration of the mouse mammary tumor virus. It is thought to play a role in intercellular communication and seems to be a signalling molecule important in the development of the central nervous system (CNS). The sequence of wnt-1 is highly conserved in mammals, fish, and amphibians. Wnt-1 was found to be a member of a large family of related proteins (Nusse R., et al., Cell (1992) 69:1073; McMahon A. P., Trends Genet. (1992) 8:1; Moon R. T., BioEssays (1993) 15:91) that are all thought to be developmental regulators. These proteins are known as wnt-2 (also known as irp), wnt-3, -3A, -4, -5A, -5B, -6, -7A, -7B, -8, -8B, -9 and -10. At least four members of this family are present in Drosophila; one of them, wingless (wg), is implicated in segmentation polarity. All these proteins share the following features characteristics of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines that are probably involved in disulfide bonds. The Wnt proteins seem to adhere to the plasma membrane of the secreting cells and are therefore likely to signal over only few cell diameters. The consensus pattern, which is based upon a highly conserved region including three cysteines, is as follows: C-K-C-H-G-[LIVMT]-S-G-x-C. All sequences known to belong to this family are detected by the provided consensus pattern.

s) Ww/rsp5/WWP Domain-Containing Proteins. SEQ ID NOS:188, 379, and 395 represent polynucleotides encoding a polypeptide in the family of WW/rsp5/WWP domain-containing proteins. The WW domain (Bork et al., Trends Biochem. Sci. (1994) 19:531; Andre et al., Biochem. Biophys. Res. Commun. (1994) 205:1201; Hofmann et al., FEBS Lett. (1995) 358:153; and Sudol et al., FEBS Lett. (1995) 369:67), also known as rsp5 or WWP), was originally discovered as a short conserved region in a number of unrelated proteins, among them dystrophin, the gene responsible for Duchenne muscular dystrophy. The domain, which spans about 35 residues, is repeated up to 4 times in some proteins. It has been shown (Chen et al., Proc. Natl. Acad. Sci. USA (1995) 92:7819) to bind proteins with particular proline-motifs, [AP]-P-P-[AP]-Y, and thus resembles somewhat SH3 domains. It appears to contain beta-strands grouped around four conserved aromatic positions, generally Trp. The name WW or WWP derives from the presence of these Trp as well as that of a conserved Pro. It is frequently associated with other domains typical for proteins in signal transduction processes.

Proteins containing the WW domain include:

1. Dystrophin, a multidomain cytoskeletal protein. Its longest alternatively spliced form consists of an N-terminal actin-binding domain, followed by 24 spectrin-like repeats, a cysteine-rich calcium-binding domain and a C-terminal globular domain. Dystrophins form tetramers and is thought to have multiple functions including involvement in membrane stability, transduction of contractile forces to the extracellular environment and organization of membrane specialization. Mutations in the dystrophin gene lead to muscular dystrophy of Duchenne or Becker type. Dystrophin contains one WW domain C-terminal of the spectrin-repeats.

2. Vertebrate YAP protein, which is a substrate of an unknown serine kinase. It binds to the SH3 domain of the Yes oncoprotein via a proline-rich region. This protein appears in alternatively spliced isoforms, containing either one or two WW domains.

3. IQGAP, which is a human GTPase activating protein acting on ras. It contains an N-terminal domain similar to fly muscle mp20 protein and a C-terminal ras GTPase activator domain.

For the sensitive detection of WW domains, the profile spans the whole homology region as well as a pattern.

t) Zinc Finger, C2H2 Type. SEQ ID NO:61, 306, and 386 correspond to polynucleotides encoding novel members of the of the C2H2 type zinc finger protein family. Zinc finger domains (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller et al, EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99) are nucleic acid-binding protein structures first identified in the Xenopus transcription factor TFIIIA. These domains have since been found in numerous nucleic acid-binding proteins. A zinc finger domain is composed of 25 to 30 amino acid residues. Two cysteine or histidine residues are positioned at both extremities of the domain, which are involved in the tetrahedral coordination of a zinc atom. It has been proposed that such a domain interacts with about five nucleotides.

Many classes of zinc fingers are characterized according to the number and positions of the histidine and cysteine residues involved in the zinc atom coordination. In the first class to be characterized, called C2H2, the first pair of zinc coordinating residues are cysteines, while the second pair are histidines. A number of experimental reports have demonstrated the zinc-dependent DNA or RNA binding property of some members of this class.

Mammalian proteins having a C2H2 zipper include (number in parenthesis indicates number of zinc finger regions in the protein): basonuclin (6), BCL-6/LAZ-3 (6), erythroid krueppel-like transcription factor (3), transcription factors Sp1 (3), Sp2 (3), Sp3 (3) and Sp(4) 3, transcriptional repressor YY1 (4), Wilms' tumor protein (4), EGR1/Krox24 (3), EGR2/Krox20 (3), EGR3/Pilot (3), EGR4/AT133 (4), Evi-1 (10), GLI1 (5), GLI2 (4+), GLI3 (3+), HIV-EP1/ZNF40 (4), HIV-EP2 (2), KR1 (9+), KR2 (9), KR3 (15+), KR4 (14+), KR5 (11+), HF.12 (6+), REX-1 (4), ZfX (13), ZfY (13), Zfp-35 (18), ZNF7 (15), ZNF8 (7), ZNF35 (10), ZNF42/MZF-1 (13), ZNF43 (22), ZNF46/Kup (2), ZNF76 (7), ZNF91 (36), ZNF133 (3).

In addition to the conserved zinc ligand residues, it has been shown that a number of other positions are also important for the structural integrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved position is found four residues after the second cysteine; it is generally an aromatic or aliphatic residue. The consensus pattern for C2H2 zinc fingers is: C-x(2,4)-C-x(3)-[LIVMFYWC]-x(8)-H-x(3,5)-H. The two C's and two H's are zinc ligands.

u) Zinc Finger, CCHC Class. SEQ ID NO:322 corresponds to a polynucleotide encoding a novel member of the zinc finger CCHC family. The CCHC zinc finger protein family to date has been mostly composed of retroviral gag proteins (nucleocapsid). The prototype structure of this family is from HIV. The family also contains members involved in eukaryotic gene regulation, such as C. elegans GLH-1. The consensus sequence of this family is based upon the common structure of an 18-residue zinc finger.

v) Zinc-Binding Metalloprotease Domain. SEQ ID NO:306 and 395 represent polynucleotides encoding novel members of the zinc-binding metalloprotease domain protein family. The majority of zinc-dependent metallopeptidases (with the notable exception of the carboxypeptidases) share a common pattern of primary structure (Jongeneel et al., FEBS Lett. (1989) 242:211; Murphy et al., FEBS Lett. (1991) 289:4; and Bode et al., Zoology (1996) 99:237) in the part of their sequence involved in the binding of zinc, and can be grouped together as a superfamily, known as the metzincins, on the basis of this sequence similarity. Examples of these proteins include: 1) Angiotensin-converting enzyme (EC 3.4.15.1) (dipeptidyl carboxypeptidase I) (ACE), the enzyme responsible for hydrolyzing angiotensin I to angiotensin II. 2) Mammalian extracellular matrix metalloproteinases (known as matrixins) (Woessner, FASEB J. (1991) 5:2145): MMP-1 (EC 3.4.24.7) (interstitial collagenase), MMP-2 (EC 3.4.24.24) (72 Kd gelatinase), MMP-9 (EC 3.4.24.35) (92 Kd gelatinase), MMP-7 (EC 3.4.24.23) (matrylisin), MMP-8 (EC 3.4.24.34) (neutrophil collagenase), MMP-3 (EC 3.4.24.17) (stromelysin-1), MMP-10 (EC 3.4.24.22) (stromelysin-2), and MMP-11 (stromelysin-3), MMP-12 (EC 3.4.24.65) (macrophage metalloelastase). 3) Endothelin-converting enzyme 1 (EC 3.4.24.71) (ECE-1), which processes the precursor of endothelin to release the active peptide.

Example 4 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 4 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 4 Description of cDNA Libraries Number of Clones Library in this (lib #) Description Clustering 1 Km12 L4 307133 Human Colon Cell Line, High Metastatic Potential (derived from Km12C) “High Colon” 2 Km12C 284755 Human Colon Cell Line, Low Metastatic Potential “Low Colon” 3 MDA-MB-231 326937 Human Breast Cancer Cell Line, High Metastatic Potential; micro-metastases in lung “High Breast” 4 MCF7 318979 Human Breast Cancer Cell, Non Metastatic “Low Breast” 8 MV-522 223620 Human Lung Cancer Cell Line, High Metastatic Potential “High Lung” 9 UCP-3 312503 Human Lung Cancer Cell Line, Low Metastatic Potential “Low Lung” 12 Human microvascular endothelial cells (HMEC) - 41938 Untreated PCR (OligodT) cDNA library 13 Human microvascular endothelial cells (HMEC) - 42100 bFGF treated PCR (OligodT) cDNA library 14 Human microvascular endothelial cells (HMEC) - 42825 VEGF treated PCR (OligodT) cDNA library 15 Normal Colon - UC#2 Patient 34285 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 16 Colon Tumor - UC#2 Patient 35625 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 17 Liver Metastasis from Colon Tumor of UC#2 36984 Patient PCR (OligodT) cDNA library “High Colon Metastasis Tissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 19 Colon Tumor - UC#3 Patient 41388 PCR (OligodT) cDNA library “High Colon Tumor Tissue” 20 Liver Metastasis from Colon Tumor of UC#3 30956 Patient PCR (OligodT) cDNA library “High Colon Metastasis Tissue”

The KM12L4 and KM12C cell lines are described in Example 1 above. The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3).

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974).

Tables 5 to 7 (inserted before the claims) show the number of clones in each of the above libraries that were analyzed for differential expression. Examples of differentially expressed polynucleotides of particular interest are described in more detail below.

TABLE 5 Cluster Clones in Clones in Clones in Clones in Clones in Clones Clone Name ID Lib1 Lib2 Lib3 Lib4 Lib8 in Lib9 M00001340B:A06 17062 3 0 0 0 0 0 M00001340D:F10 11589 2 2 1 3 3 8 M00001341A:E12 4443 10 6 2 6 3 11 M00001342B:E06 39805 2 0 0 0 1 0 M00001343C:F10 2790 7 15 13 14 6 0 M00001343D:H07 23255 3 0 1 1 0 0 M00001345A:E01 6420 8 0 2 0 1 0 M00001346A:F09 5007 4 8 3 6 2 6 M00001346D:E03 6806 5 2 1 2 0 3 M00001346D:G06 5779 5 4 3 4 0 0 M00001346D:G06 5779 5 4 3 4 0 0 M00001347A:B10 13576 5 0 0 0 12 11 M00001348B:B04 16927 4 0 0 2 0 0 M00001348B:G06 16985 4 0 0 0 0 0 M00001349B:B08 3584 5 11 5 0 0 2 M00001350A:H01 7187 5 3 1 0 1 0 M00001351B:A08 3162 10 14 1 6 6 5 M00001351B:A08 3162 10 14 1 6 6 5 M00001352A:E02 16245 4 0 0 0 0 0 M00001353A:G12 8078 4 3 1 0 1 0 M00001353D:D10 14929 4 0 0 1 23 16 M00001355B:G10 14391 3 1 0 0 0 0 M00001357D:D11 4059 8 6 8 16 0 1 M00001361A:A05 4141 5 2 10 16 4 27 M00001361D:F08 2379 26 13 4 2 2 3 M00001362B:D10 5622 7 4 2 13 1 2 M00001362C:H11 945 9 21 2 1 0 0 M00001365C:C10 40132 2 0 0 0 3 0 M00001370A:C09 6867 7 3 0 0 0 0 M00001371C:E09 7172 3 5 1 2 0 1 M00001376B:G06 17732 1 3 5 0 1 4 M00001378B:B02 39833 2 0 0 0 0 0 M00001379A:A05 1334 27 38 35 28 3 0 M00001380D:B09 39886 2 0 0 0 0 0 M00001382C:A02 22979 2 1 0 0 0 0 M00001383A:C03 39648 2 0 0 0 0 0 M00001383A:C03 39648 2 0 0 0 0 0 M00001386C:B12 5178 5 5 4 2 5 2 M00001387A:C05 2464 5 19 25 16 1 0 M00001387B:G03 7587 6 2 1 0 0 0 M00001388D:G05 5832 10 3 0 1 5 0 M00001389A:C08 16269 3 0 0 0 1 1 M00001394A:F01 6583 2 7 3 2 0 0 M00001395A:C03 4016 5 14 0 6 0 0 M00001396A:C03 4009 6 4 13 5 4 10 M00001402A:E08 39563 2 0 0 0 0 0 M00001407B:D11 5556 8 1 5 0 2 0 M00001409C:D12 9577 5 2 0 1 11 12 M00001410A:D07 7005 8 2 0 0 0 0 M00001412B:B10 8551 4 4 0 3 0 0 M00001415A:H06 13538 5 0 0 0 9 1 M00001416A:H01 7674 5 2 0 5 0 0 M00001416B:H11 8847 4 1 3 0 6 1 M00001417A:E02 36393 2 0 0 1 0 0 M00001418B:F03 9952 4 2 1 1 0 0 M00001418D:B06 8526 3 2 1 5 1 0 M00001421C:F01 9577 5 2 0 1 11 12 M00001423B:E07 15066 4 0 0 0 0 0 M00001424B:G09 10470 5 1 0 2 0 1 M00001425B:H08 22195 3 0 0 0 0 0 M00001426D:C08 4261 4 9 7 9 12 15 M00001428A:H10 84182 1 0 0 0 0 0 M00001429A:H04 2797 15 11 18 16 1 14 M00001429B:A11 4635 7 9 2 0 0 0 M00001429D:D07 40392 2 0 1 8 12 16 M00001439C:F08 40054 1 0 0 0 0 0 M00001442C:D07 16731 3 1 0 0 0 0 M00001445A:F05 13532 3 2 1 0 1 2 M00001446A:F05 7801 5 2 4 6 1 0 M00001447A:G03 10717 7 2 0 5 8 0 M00001448D:C09 8 1850 2127 1703 3133 1355 122 M00001448D:H01 36313 2 0 0 0 1 30 M00001449A:A12 5857 6 2 3 4 0 0 M00001449A:B12 41633 1 1 0 0 0 0 M00001449A:D12 3681 12 5 10 1 2 5 M00001449A:G10 36535 2 0 0 0 0 0 M00001449C:D06 86110 1 0 0 0 0 0 M00001450A:A02 39304 2 0 0 0 0 0 M00001450A:A11 32663 1 1 0 0 0 0 M00001450A:B12 82498 1 0 0 0 0 0 M00001450A:D08 27250 2 0 0 0 0 0 M00001452A:B04 84328 1 0 0 0 0 0 M00001452A:B12 86859 1 0 0 0 0 0 M00001452A:D08 1120 44 41 5 11 5 0 M00001452A:F05 85064 1 0 0 0 0 0 M00001452C:B06 16970 4 0 0 0 3 4 M00001453A:E11 16130 3 1 0 0 0 1 M00001453C:F06 16653 3 1 0 0 0 0 M00001454A:A09 83103 1 0 0 0 0 0 M00001454B:C12 7005 8 2 0 0 0 0 M00001454D:G03 689 58 95 17 36 66 95 M00001455A:E09 13238 4 1 0 0 0 0 M00001455B:E12 13072 4 1 0 0 0 0 M00001455D:F09 9283 4 1 0 1 0 1 M00001455D:F09 9283 4 1 0 1 0 1 M00001460A:F06 2448 23 22 2 3 3 1 M00001460A:F12 39498 2 0 0 0 0 0 M00001461A:D06 1531 20 23 32 17 14 14 M00001463C:B11 19 1415 1203 1364 525 479 774 M00001465A:B11 10145 2 0 2 0 0 0 M00001466A:E07 4275 11 2 5 0 4 2 M00001467A:B07 38759 2 0 0 0 1 1 M00001467A:D04 39508 2 0 0 0 0 0 M00001467A:D08 16283 3 0 0 0 0 0 M00001467A:D08 16283 3 0 0 0 0 0 M00001467A:E10 39442 2 0 0 0 0 0 M00001468A:F05 7589 6 2 1 1 1 0 M00001469A:C10 12081 4 0 0 0 0 0 M00001469A:H12 19105 2 0 2 0 1 0 M00001470A:B10 1037 53 48 4 22 0 0 M00001470A:C04 39425 2 0 0 0 0 0 M00001471A:B01 39478 2 0 0 0 0 0 M00001481D:A05 7985 3 1 4 0 1 0 M00001490B:C04 18699 2 1 0 0 0 3 M00001494D:F06 7206 4 3 3 1 2 0 M00001497A:G02 2623 12 4 31 4 6 1 M00001499B:A11 10539 2 1 1 0 1 0 M00001500A:C05 5336 9 2 4 8 3 15 M00001500A:E11 2623 12 4 31 4 6 1 M00001500C:E04 9443 4 2 1 1 0 0 M00001501D:C02 9685 3 2 0 7 2 3 M00001504C:A07 10185 5 1 0 0 2 4 M00001504C:H06 6974 7 3 0 1 0 0 M00001504D:G06 6420 8 0 2 0 1 0 M00001507A:H05 39168 2 0 0 0 0 0 M00001511A:H06 39412 2 0 0 0 0 0 M00001512A:A09 39186 2 0 0 0 0 0 M00001512D:G09 3956 9 9 5 2 0 0 M00001513A:B06 4568 10 4 0 9 2 0 M00001513C:E08 14364 1 0 0 0 0 0 M00001514C:D11 40044 2 0 0 0 0 0 M00001517A:B07 4313 13 6 1 0 1 0 M00001518C:B11 8952 3 4 0 4 2 0 M00001528A:C04 7337 4 4 3 16 12 21 M00001528A:F09 18957 3 0 0 0 0 0 M00001528B:H04 8358 3 3 2 0 0 0 M00001531A:D01 38085 2 0 0 0 0 0 M00001532B:A06 3990 6 12 4 1 3 1 M00001533A:C11 2428 14 14 13 9 2 19 M00001534A:C04 16921 4 0 0 1 2 1 M00001534A:D09 5097 6 5 1 1 3 2 M00001534A:F09 5321 11 7 1 5 10 26 M00001534C:A01 4119 9 4 2 2 5 3 M00001535A:B01 7665 3 1 5 0 0 0 M00001535A:C06 20212 2 0 1 1 0 0 M00001535A:F10 39423 2 0 0 0 0 0 M00001536A:B07 2696 23 11 9 18 10 21 M00001536A:C08 39392 2 0 0 0 0 0 M00001537A:F12 39420 2 0 0 0 0 0 M00001537B:G07 3389 4 11 13 2 0 0 M00001540A:D06 8286 6 1 0 3 4 0 M00001541A:D02 3765 19 6 0 0 0 0 M00001541A:F07 22085 3 0 0 0 0 1 M00001541A:H03 39174 2 0 0 0 0 0 M00001542A:A09 22113 3 0 0 0 0 0 M00001542A:E06 39453 2 0 0 0 0 0 M00001544A:E03 12170 2 1 2 0 0 0 M00001544A:G02 19829 2 0 1 0 0 0 M00001544B:B07 6974 7 3 0 1 0 0 M00001545A:C03 19255 2 0 0 0 0 0 M00001545A:D08 13864 3 0 2 1 2 4 M00001546A:G11 1267 43 55 5 0 0 0 M00001548A:E10 5892 5 1 4 4 1 3 M00001548A:H09 1058 40 44 37 47 39 59 M00001549A:B02 4015 10 5 8 15 2 0 M00001549A:D08 10944 3 0 3 1 0 7 M00001549B:F06 4193 12 7 2 2 0 1 M00001549C:E06 16347 4 0 0 0 0 0 M00001550A:A03 7239 5 2 1 0 2 0 M00001550A:G01 5175 8 1 3 2 0 0 M00001551A:B10 6268 6 4 3 18 5 0 M00001551A:F05 39180 2 0 0 0 0 0 M00001551A:G06 22390 2 1 0 0 0 1 M00001551C:G09 3266 12 14 0 1 0 6 M00001552A:B12 307 73 60 196 75 79 27 M00001552A:D11 39458 2 0 0 0 0 0 M00001552B:D04 5708 5 4 4 3 1 4 M00001553A:H06 8298 4 3 1 3 0 0 M00001553B:F12 4573 5 7 2 5 0 1 M00001553D:D10 22814 3 0 0 0 0 0 M00001555A:B02 39539 2 0 0 0 1 0 M00001555A:C01 39195 2 0 0 0 0 0 M00001555D:G10 4561 8 4 4 8 0 0 M00001556A:C09 9244 2 0 3 2 10 17 M00001556A:F11 1577 12 40 25 3 4 0 M00001556A:H01 15855 2 1 1 2 12 213 M00001556B:C08 4386 7 8 3 1 3 21 M00001556B:G02 11294 4 0 2 0 0 1 M00001557A:D02 7065 5 3 2 1 0 0 M00001557A:D02 7065 5 3 2 1 0 0 M00001557A:F01 9635 3 0 2 1 0 0 M00001557A:F03 39490 2 0 0 0 1 0 M00001557B:H10 5192 8 5 0 5 0 0 M00001557D:D09 8761 3 4 0 1 0 1 M00001558B:H11 7514 5 3 0 0 0 0 M00001560D:F10 6558 4 3 4 0 0 5 M00001561A:C05 39486 2 0 0 0 0 0 M00001563B:F06 102 289 233 278 116 123 184 M00001564A:B12 5053 11 4 2 2 1 1 M00001571C:H06 5749 4 1 9 0 0 0 M00001578B:E04 23001 2 1 0 2 0 0 M00001579D:C03 6539 8 3 0 0 0 1 M00001583D:A10 6293 3 5 2 6 0 0 M00001586C:C05 4623 3 4 12 2 1 1 M00001587A:B11 39380 2 0 0 0 0 0 M00001594B:H04 260 189 188 27 2 15 0 M00001597C:H02 4837 6 2 10 0 3 1 M00001597D:C05 10470 5 1 0 2 0 1 M00001598A:G03 16999 4 0 0 0 0 0 M00001601A:D08 22794 2 0 0 0 0 0 M00001604A:B10 1399 49 27 19 7 10 23 M00001604A:F05 39391 2 0 0 0 0 0 M00001607A:E11 11465 5 0 0 0 0 0 M00001608A:B03 7802 5 4 0 1 0 0 M00001608B:E03 22155 3 0 0 0 0 0 M00001614C:F10 13157 4 1 0 3 1 0 M00001617C:E02 17004 4 0 1 0 1 0 M00001619C:F12 40314 2 0 0 0 1 0 M00001621C:C08 40044 2 0 0 0 0 0 M00001623D:F10 13913 2 1 2 0 0 1 M00001624A:B06 3277 10 11 8 3 5 1 M00001624C:F01 4309 4 13 3 10 0 0 M00001630B:H09 5214 10 2 2 2 4 3 M00001644C:B07 39171 2 0 0 0 0 0 M00001645A:C12 19267 2 0 0 0 0 1 M00001648C:A01 4665 5 9 0 0 0 0 M00001657D:C03 23201 3 0 0 0 3 0 M00001657D:F08 76760 1 0 2 2 0 5 M00001662C:A09 23218 3 0 0 0 0 0 M00001663A:E04 35702 2 0 0 0 0 0 M00001669B:F02 6468 4 3 3 8 1 0 M00001670C:H02 14367 3 0 0 0 0 0 M00001673C:H02 7015 6 3 1 2 1 1 M00001675A:C09 8773 4 1 4 4 4 6 M00001676B:F05 11460 4 2 0 0 0 0 M00001677C:E10 14627 1 2 1 0 1 0 M00001677D:A07 7570 5 3 0 0 0 0 M00001678D:F12 4416 9 5 2 6 1 3 M00001679A:A06 6660 7 0 4 2 1 0 M00001679A:F10 26875 1 0 0 0 1 0 M00001679B:F01 6298 2 4 5 3 1 0 M00001679C:F01 78091 1 0 0 0 0 0 M00001679D:D03 10751 3 2 0 1 0 1 M00001679D:D03 10751 3 2 0 1 0 1 M00001680D:F08 10539 2 1 1 0 1 0 M00001682C:B12 17055 4 0 0 0 0 0 M00001686A:E06 4622 7 6 4 2 3 0 M00001688C:F09 5382 6 2 6 2 0 3 M00001693C:G01 4393 10 6 2 4 1 1 M00001716D:H05 67252 1 0 0 1 0 0 M00003741D:C09 40108 2 0 0 0 0 0 M00003747D:C05 11476 6 0 0 0 0 0 M00003759B:B09 697 76 52 30 72 21 30 M00003762C:B08 17076 4 0 0 0 0 0 M00003763A:F06 3108 14 11 7 5 0 1 M00003774C:A03 67907 1 0 0 0 0 0 M00003796C:D05 5619 3 5 3 3 0 4 M00003826B:A06 11350 3 3 0 0 1 0 M00003833A:E05 21877 2 1 0 0 0 1 M00003837D:A01 7899 5 4 0 2 1 0 M00003839A:D08 7798 5 2 2 0 0 1 M00003844C:B11 6539 8 3 0 0 0 1 M00003846B:D06 6874 6 3 0 0 0 0 M00003851B:D10 13595 4 0 1 0 0 1 M00003853A:D04 5619 3 5 3 3 0 4 M00003853A:F12 10515 5 1 0 1 1 2 M00003856B:C02 4622 7 6 4 2 3 0 M00003857A:G10 3389 4 11 13 2 0 0 M00003857A:H03 4718 4 5 5 2 4 6 M00003871C:E02 4573 5 7 2 5 0 1 M00003875B:F04 12977 5 0 0 0 0 0 M00003875B:F04 12977 5 0 0 0 0 0 M00003875C:G07 8479 4 3 1 1 2 4 M00003876D:E12 7798 5 2 2 0 0 1 M00003879B:C11 5345 7 1 7 4 6 27 M00003879B:D10 31587 1 1 0 0 1 0 M00003879D:A02 14507 3 1 0 0 3 1 M00003885C:A02 13576 5 0 0 0 12 11 M00003885C:A02 13576 5 0 0 0 12 11 M00003906C:E10 9285 4 3 0 0 1 2 M00003907D:A09 39809 1 0 0 0 2 1 M00003907D:H04 16317 3 0 0 0 0 0 M00003909D:C03 8672 4 4 0 0 0 0 M00003912B:D01 12532 4 1 0 1 0 1 M00003914C:F05 3900 9 6 8 1 7 13 M00003922A:E06 23255 3 0 1 1 0 0 M00003958A:H02 18957 3 0 0 0 0 0 M00003958A:H02 18957 3 0 0 0 0 0 M00003958C:G10 40455 2 0 0 0 0 0 M00003958C:G10 40455 2 0 0 0 0 0 M00003968B:F06 24488 2 0 1 4 0 0 M00003970C:B09 40122 2 0 0 0 0 0 M00003974D:E07 23210 3 0 0 0 0 0 M00003974D:H02 23358 3 0 0 0 1 0 M00003975A:G11 12439 4 0 0 0 0 0 M00003978B:G05 5693 7 4 1 3 1 1 M00003981A:E10 3430 9 10 7 3 0 0 M00003982C:C02 2433 10 13 21 18 8 8 M00003983A:A05 9105 5 1 1 1 0 0 M00004028D:A06 6124 4 8 1 9 1 0 M00004028D:C05 40073 2 0 1 0 0 1 M00004031A:A12 9061 5 2 0 0 0 0 M00004031A:A12 9061 5 2 0 0 0 0 M00004035C:A07 37285 2 0 0 1 0 1 M00004035D:B06 17036 4 0 0 0 0 0 M00004059A:D06 5417 10 4 0 9 2 0 M00004068B:A01 3706 7 14 4 22 1 0 M00004072B:B05 17036 4 0 0 0 0 0 M00004081C:D10 15069 3 0 0 1 0 0 M00004081C:D12 14391 3 1 0 0 0 0 M00004086D:G06 9285 4 3 0 0 1 2 M00004087D:A01 6880 2 6 1 1 0 0 M00004093D:B12 5325 5 5 2 0 2 1 M00004093D:B12 5325 5 5 2 0 2 1 M00004105C:A04 7221 5 2 2 2 0 0 M00004108A:E06 4937 4 9 3 1 3 1 M00004111D:A08 6874 6 3 0 0 0 0 M00004114C:F11 13183 2 3 0 7 0 1 M00004138B:H02 13272 3 2 0 3 0 0 M00004146C:C11 5257 2 8 5 5 5 25 M00004151D:B08 16977 4 0 0 0 0 0 M00004157C:A09 6455 3 1 6 0 0 0 M00004169C:C12 5319 6 2 8 2 2 3 M00004171D:B03 4908 6 7 2 2 2 0 M00004172C:D08 11494 4 0 0 0 0 0 M00004183C:D07 16392 3 0 0 0 0 0 M00004185C:C03 11443 5 1 0 0 0 0 M00004197D:H01 8210 2 6 0 0 0 0 M00004203B:C12 14311 4 0 0 0 1 2 M00004212B:C07 2379 26 13 4 2 2 3 M00004214C:H05 11451 3 2 1 2 1 1 M00004223A:G10 16918 4 0 0 0 0 0 M00004223B:D09 7899 5 4 0 2 1 0 M00004223D:E04 12971 4 0 0 0 1 0 M00004229B:F08 6455 3 1 6 0 0 0 M00004230B:C07 7212 3 5 2 1 3 0 M00004269D:D06 4905 7 6 3 1 3 1 M00004275C:C11 16914 3 0 0 1 0 0 M00004283B:A04 14286 3 1 0 1 1 1 M00004285B:E08 56020 1 0 0 0 0 0 M00004295D:F12 16921 4 0 0 1 2 1 M00004296C:H07 13046 4 1 0 1 0 0 M00004307C:A06 9457 2 0 5 0 3 0 M00004312A:G03 26295 2 0 0 0 0 0 M00004318C:D10 21847 2 1 0 0 0 0 M00004372A:A03 2030 13 10 32 4 0 0 M00004377C:F05 2102 12 20 23 21 6 5

TABLE 6 Clones in Clones in Clones in Clones in Clones in Clones in Clone Name Cluster ID Lib15 Lib16b Lib17 Lib18 Lib19 Lib20 M00001340B:A06 17062 0 0 0 0 0 0 M00001340D:F10 11589 0 0 0 0 0 0 M00001341A:E12 4443 0 0 0 1 0 0 M00001342B:E06 39805 0 0 0 0 0 0 M00001343C:F10 2790 0 0 0 0 0 0 M00001343D:H07 23255 0 0 0 0 0 0 M00001345A:E01 6420 0 0 0 0 0 0 M00001346A:F09 5007 0 0 0 0 0 0 M00001346D:E03 6806 0 0 0 0 0 0 M00001346D:G06 5779 0 0 0 0 0 0 M00001346D:G06 5779 0 0 0 0 0 0 M00001347A:B10 13576 0 0 0 0 0 0 M00001348B:B04 16927 0 0 0 0 0 0 M00001348B:G06 16985 0 0 0 0 0 0 M00001349B:B08 3584 0 0 0 0 0 0 M00001350A:H01 7187 0 0 0 0 0 0 M00001351B:A08 3162 0 1 0 0 1 0 M00001351B:A08 3162 0 1 0 0 1 0 M00001352A:E02 16245 0 0 0 0 0 0 M00001353A:G12 8078 0 0 0 0 0 0 M00001353D:D10 14929 0 3 1 0 5 0 M00001355B:G10 14391 0 0 0 0 0 0 M00001357D:D11 4059 0 0 0 0 0 0 M00001361A:A05 4141 0 0 0 0 0 0 M00001361D:F08 2379 0 0 0 0 0 0 M00001362B:D10 5622 0 0 0 0 0 0 M00001362C:H11 945 0 0 0 0 0 1 M00001365C:C10 40132 0 0 0 0 0 0 M00001370A:C09 6867 0 0 0 0 0 0 M00001371C:E09 7172 0 0 0 0 0 0 M00001376B:G06 17732 0 0 0 0 0 1 M00001378B:B02 39833 0 0 0 0 0 0 M00001379A:A05 1334 0 0 0 0 0 1 M00001380D:B09 39886 0 0 0 0 0 0 M00001382C:A02 22979 0 0 0 0 0 0 M00001383A:C03 39648 0 0 0 0 0 0 M00001383A:C03 39648 0 0 0 0 0 0 M00001386C:B12 5178 0 0 0 0 0 0 M00001387A:C05 2464 0 0 0 0 0 0 M00001387B:G03 7587 0 0 0 0 0 0 M00001388D:G05 5832 0 0 0 0 0 0 M00001389A:C08 16269 0 1 0 0 0 0 M00001394A:F01 6583 1 4 1 0 0 0 M00001395A:C03 4016 0 0 0 0 0 0 M00001396A:C03 4009 0 0 0 0 0 0 M00001402A:E08 39563 0 0 0 0 0 0 M00001407B:D11 5556 0 0 0 0 0 0 M00001409C:D12 9577 0 0 0 0 0 0 M00001410A:D07 7005 0 0 0 0 0 0 M00001412B:B10 8551 0 0 0 0 0 0 M00001415A:H06 13538 0 0 0 0 0 0 M00001416A:H01 7674 0 0 0 0 0 0 M00001416B:H11 8847 0 0 0 0 0 0 M00001417A:E02 36393 0 0 0 0 0 0 M00001418B:F03 9952 0 0 0 0 0 0 M00001418D:B06 8526 0 0 0 0 0 0 M00001421C:F01 9577 0 0 0 0 0 0 M00001423B:E07 15066 0 0 0 0 0 0 M00001424B:G09 10470 0 0 0 0 0 0 M00001425B:H08 22195 0 0 0 0 0 0 M00001426D:C08 4261 0 0 1 0 0 1 M00001428A:H10 84182 0 0 0 0 0 0 M00001429A:H04 2797 0 0 0 0 0 0 M00001429B:A11 4635 0 0 0 0 0 0 M00001429D:D07 40392 0 0 0 0 0 0 M00001439C:F08 40054 0 0 0 0 0 0 M00001442C:D07 16731 0 0 0 0 0 0 M00001445A:F05 13532 0 0 0 0 0 0 M00001446A:F05 7801 0 0 0 0 0 0 M00001447A:G03 10717 0 0 0 0 0 0 M00001448D:C09 8 1 6 6 1 14 1 M00001448D:H01 36313 0 3 0 0 3 0 M00001449A:A12 5857 0 0 0 0 0 0 M00001449A:B12 41633 0 0 0 0 0 0 M00001449A:D12 3681 0 0 0 0 0 0 M00001449A:G10 36535 0 0 0 0 0 0 M00001449C:D06 86110 0 0 0 0 0 0 M00001450A:A02 39304 0 0 0 0 0 0 M00001450A:A11 32663 0 0 0 0 0 0 M00001450A:B12 82498 0 0 0 0 0 0 M00001450A:D08 27250 0 0 0 0 0 0 M00001452A:B04 84328 0 0 0 0 0 0 M00001452A:B12 86859 0 0 0 0 0 0 M00001452A:D08 1120 0 0 0 0 0 0 M00001452A:F05 85064 0 0 0 0 0 0 M00001452C:B06 16970 0 0 2 0 1 0 M00001453A:E11 16130 0 0 0 0 0 0 M00001453C:F06 16653 0 0 0 0 0 0 M00001454A:A09 83103 0 0 0 0 0 0 M00001454B:C12 7005 0 0 0 0 0 0 M00001454D:G03 689 0 2 2 0 4 2 M00001455A:E09 13238 0 0 0 0 0 0 M00001455B:E12 13072 0 0 0 0 0 0 M00001455D:F09 9283 0 0 0 0 0 0 M00001455D:F09 9283 0 0 0 0 0 0 M00001460A:F06 2448 0 0 0 0 0 0 M00001460A:F12 39498 0 0 0 0 0 0 M00001461A:D06 1531 0 0 0 0 0 0 M00001463C:B11 19 2 13 13 0 69 10 M00001465A:B11 10145 0 0 0 0 0 0 M00001466A:E07 4275 0 0 0 0 0 0 M00001467A:B07 38759 0 0 0 0 0 0 M00001467A:D04 39508 0 0 0 0 0 0 M00001467A:D08 16283 0 0 0 0 0 0 M00001467A:D08 16283 0 0 0 0 0 0 M00001467A:E10 39442 0 0 0 0 0 0 M00001468A:F05 7589 0 0 0 0 0 0 M00001469A:C10 12081 0 0 0 0 0 0 M00001469A:H12 19105 0 0 0 0 0 0 M00001470A:B10 1037 0 0 0 0 0 0 M00001470A:C04 39425 0 0 0 0 0 0 M00001471A:B01 39478 0 0 0 0 0 0 M00001481D:A05 7985 0 0 0 0 0 0 M00001490B:C04 18699 0 0 0 0 0 0 M00001494D:F06 7206 0 0 0 0 0 0 M00001497A:G02 2623 0 0 0 0 0 0 M00001499B:A11 10539 0 0 0 0 0 0 M00001500A:C05 5336 0 0 0 0 0 0 M00001500A:E11 2623 0 0 0 0 0 0 M00001500C:E04 9443 0 0 0 0 0 0 M00001501D:C02 9685 0 0 0 0 0 0 M00001504C:A07 10185 0 0 0 0 0 0 M00001504C:H06 6974 0 0 0 0 0 0 M00001504D:G06 6420 0 0 0 0 0 0 M00001507A:H05 39168 0 0 0 0 0 0 M00001511A:H06 39412 0 0 0 0 0 0 M00001512A:A09 39186 0 0 0 0 0 0 M00001512D:G09 3956 0 0 1 0 0 0 M00001513A:B06 4568 0 0 0 0 0 0 M00001513C:E08 14364 0 0 0 0 0 0 M00001514C:D11 40044 0 1 0 0 0 0 M00001517A:B07 4313 0 0 0 0 0 0 M00001518C:B11 8952 0 0 0 0 0 0 M00001528A:C04 7337 0 0 0 0 0 0 M00001528A:F09 18957 0 0 0 0 0 0 M00001528B:H04 8358 0 0 0 0 0 0 M00001531A:D01 38085 0 0 0 0 0 0 M00001532B:A06 3990 1 1 0 0 0 0 M00001533A:C11 2428 0 0 1 0 0 0 M00001534A:C04 16921 0 0 0 0 0 0 M00001534A:D09 5097 0 0 0 0 0 0 M00001534A:F09 5321 0 1 0 0 2 0 M00001534C:A01 4119 0 0 0 0 0 0 M00001535A:B01 7665 0 0 0 0 0 0 M00001535A:C06 20212 0 0 0 0 0 0 M00001535A:F10 39423 0 0 0 0 0 0 M00001536A:B07 2696 0 0 0 0 3 0 M00001536A:C08 39392 0 0 0 0 0 0 M00001537A:F12 39420 0 0 0 0 0 0 M00001537B:G07 3389 0 0 0 0 0 0 M00001540A:D06 8286 0 0 0 0 0 0 M00001541A:D02 3765 0 0 0 0 0 0 M00001541A:F07 22085 0 0 0 0 0 0 M00001541A:H03 39174 0 0 0 0 0 0 M00001542A:A09 22113 0 0 0 0 0 0 M00001542A:E06 39453 0 0 0 0 0 0 M00001544A:E03 12170 0 0 0 0 0 0 M00001544A:G02 19829 0 0 0 0 0 0 M00001544B:B07 6974 0 0 0 0 0 0 M00001545A:C03 19255 0 0 0 0 0 0 M00001545A:D08 13864 0 0 0 0 0 0 M00001546A:G11 1267 1 0 0 0 7 0 M00001548A:E10 5892 0 0 0 0 0 0 M00001548A:H09 1058 0 0 1 0 0 0 M00001549A:B02 4015 0 0 0 0 0 0 M00001549A:D08 10944 0 0 0 0 0 0 M00001549B:F06 4193 0 0 0 0 0 0 M00001549C:E06 16347 0 0 0 0 0 0 M00001550A:A03 7239 0 0 0 0 0 0 M00001550A:G01 5175 0 0 0 0 0 0 M00001551A:B10 6268 0 0 0 0 0 0 M00001551A:F05 39180 0 0 0 0 0 0 M00001551A:G06 22390 0 0 0 0 0 0 M00001551C:G09 3266 0 0 1 0 0 0 M00001552A:B12 307 0 0 0 0 3 0 M00001552A:D11 39458 0 0 0 0 0 0 M00001552B:D04 5708 0 1 0 0 0 0 M00001553A:H06 8298 0 0 0 0 0 0 M00001553B:F12 4573 0 0 0 0 0 0 M00001553D:D10 22814 0 0 0 0 0 0 M00001555A:B02 39539 0 0 0 0 0 0 M00001555A:C01 39195 0 0 0 0 0 0 M00001555D:G10 4561 0 0 0 0 0 0 M00001556A:C09 9244 0 0 0 0 0 0 M00001556A:F11 1577 0 0 0 0 0 0 M00001556A:H01 15855 3 5 5 0 3 1 M00001556B:C08 4386 1 2 0 0 0 0 M00001556B:G02 11294 0 0 0 0 0 0 M00001557A:D02 7065 0 0 0 0 0 0 M00001557A:D02 7065 0 0 0 0 0 0 M00001557A:F01 9635 0 0 0 0 0 0 M00001557A:F03 39490 0 0 0 0 0 0 M00001557B:H10 5192 0 0 0 0 0 0 M00001557D:D09 8761 0 0 0 0 0 0 M00001558B:H11 7514 0 0 0 0 0 0 M00001560D:F10 6558 0 0 0 0 0 0 M00001561A:C05 39486 0 0 0 0 0 0 M00001563B:F06 102 22 38 65 7 43 10 M00001564A:B12 5053 0 0 1 0 0 0 M00001571C:H06 5749 0 0 0 0 0 0 M00001578B:E04 23001 0 0 0 0 0 0 M00001579D:C03 6539 0 0 0 0 0 0 M00001583D:A10 6293 0 0 0 0 0 0 M00001586C:C05 4623 0 0 0 0 1 0 M00001587A:B11 39380 0 0 0 0 0 0 M00001594B:H04 260 0 0 0 0 1 0 M00001597C:H02 4837 0 0 0 0 0 0 M00001597D:C05 10470 0 0 0 0 0 0 M00001598A:G03 16999 1 1 1 0 0 0 M00001601A:D08 22794 0 0 0 0 0 0 M00001604A:B10 1399 0 0 0 0 0 0 M00001604A:F05 39391 0 0 0 0 0 0 M00001607A:E11 11465 0 0 0 0 0 0 M00001608A:B03 7802 0 0 0 0 0 0 M00001608B:E03 22155 0 0 0 0 0 0 M00001614C:F10 13157 0 0 0 0 0 0 M00001617C:E02 17004 0 0 0 0 1 0 M00001619C:F12 40314 0 0 0 0 0 0 M00001621C:C08 40044 0 1 0 0 0 0 M00001623D:F10 13913 0 0 0 0 0 0 M00001624A:B06 3277 0 0 0 0 0 0 M00001624C:F01 4309 0 0 0 0 0 0 M00001630B:H09 5214 1 0 0 1 1 0 M00001644C:B07 39171 0 0 0 0 0 0 M00001645A:C12 19267 0 0 0 0 1 0 M00001648C:A01 4665 0 0 0 0 0 0 M00001657D:C03 23201 0 0 0 0 0 0 M00001657D:F08 76760 0 0 0 0 0 0 M00001662C:A09 23218 0 0 0 0 0 0 M00001663A:E04 35702 0 0 0 0 0 0 M00001669B:F02 6468 0 0 0 0 0 0 M00001670C:H02 14367 0 0 0 0 0 0 M00001673C:H02 7015 0 0 0 0 0 0 M00001675A:C09 8773 0 0 0 0 0 0 M00001676B:F05 11460 0 0 0 0 0 0 M00001677C:E10 14627 0 1 0 0 0 0 M00001677D:A07 7570 0 0 0 0 0 0 M00001678D:F12 4416 0 0 0 0 0 0 M00001679A:A06 6660 0 0 0 0 0 0 M00001679A:F10 26875 0 0 0 0 0 0 M00001679B:F01 6298 0 0 0 0 0 0 M00001679C:F01 78091 0 0 0 0 0 0 M00001679D:D03 10751 0 0 0 0 0 0 M00001679D:D03 10751 0 0 0 0 0 0 M00001680D:F08 10539 0 0 0 0 0 0 M00001682C:B12 17055 0 0 0 0 0 0 M00001686A:E06 4622 0 0 0 0 0 0 M00001688C:F09 5382 0 0 0 0 0 0 M00001693C:G01 4393 0 0 0 0 0 0 M00001716D:H05 67252 0 0 0 0 0 0 M00003741D:C09 40108 0 0 0 0 0 0 M00003747D:C05 11476 0 0 0 0 0 0 M00003759B:B09 697 0 0 0 0 1 0 M00003762C:B08 17076 0 0 0 0 0 0 M00003763A:F06 3108 0 0 0 0 0 0 M00003774C:A03 67907 0 0 0 0 0 0 M00003796C:D05 5619 0 0 0 0 0 0 M00003826B:A06 11350 0 0 0 0 0 0 M00003833A:E05 21877 0 0 0 0 0 0 M00003837D:A01 7899 0 0 0 0 0 0 M00003839A:D08 7798 0 0 0 0 0 0 M00003844C:B11 6539 0 0 0 0 0 0 M00003846B:D06 6874 0 0 1 0 0 0 M00003851B:D10 13595 0 0 0 0 0 0 M00003853A:D04 5619 0 0 0 0 0 0 M00003853A:F12 10515 0 0 0 0 0 0 M00003856B:C02 4622 0 0 0 0 0 0 M00003857A:G10 3389 0 0 0 0 0 0 M00003857A:H03 4718 0 0 0 0 0 0 M00003871C:E02 4573 0 0 0 0 0 0 M00003875B:F04 12977 0 0 0 0 0 0 M00003875B:F04 12977 0 0 0 0 0 0 M00003875C:G07 8479 0 0 0 0 0 1 M00003876D:E12 7798 0 0 0 0 0 0 M00003879B:C11 5345 0 0 0 2 0 1 M00003879B:D10 31587 0 0 0 0 0 0 M00003879D:A02 14507 0 0 0 0 0 0 M00003885C:A02 13576 0 0 0 0 0 0 M00003885C:A02 13576 0 0 0 0 0 0 M00003906C:E10 9285 0 0 0 0 0 0 M00003907D:A09 39809 0 0 0 0 0 0 M00003907D:H04 16317 0 0 0 0 0 0 M00003909D:C03 8672 0 0 0 0 0 0 M00003912B:D01 12532 0 0 0 0 0 0 M00003914C:F05 3900 0 0 0 0 1 0 M00003922A:E06 23255 0 0 0 0 0 0 M00003958A:H02 18957 0 0 0 0 0 0 M00003958A:H02 18957 0 0 0 0 0 0 M00003958C:G10 40455 0 0 0 0 0 0 M00003958C:G10 40455 0 0 0 0 0 0 M00003968B:F06 24488 0 0 0 0 0 0 M00003970C:B09 40122 0 0 0 0 0 0 M00003974D:E07 23210 0 0 0 0 0 0 M00003974D:H02 23358 0 0 0 0 0 0 M00003975A:G11 12439 0 0 0 0 0 0 M00003978B:G05 5693 0 0 0 0 0 0 M00003981A:E10 3430 0 0 0 0 1 0 M00003982C:C02 2433 0 0 0 0 0 0 M00003983A:A05 9105 0 0 0 0 0 0 M00004028D:A06 6124 0 0 0 0 0 0 M00004028D:C05 40073 0 0 0 0 0 0 M00004031A:A12 9061 0 0 0 0 0 0 M00004031A:A12 9061 0 0 0 0 0 0 M00004035C:A07 37285 0 0 0 0 0 0 M00004035D:B06 17036 0 0 0 0 0 0 M00004059A:D06 5417 0 0 0 0 0 0 M00004068B:A01 3706 0 0 0 0 0 0 M00004072B:B05 17036 0 0 0 0 0 0 M00004081C:D10 15069 0 0 0 0 0 0 M00004081C:D12 14391 0 0 0 0 0 0 M00004086D:G06 9285 0 0 0 0 0 0 M00004087D:A01 6880 0 0 0 0 0 0 M00004093D:B12 5325 1 1 0 1 0 1 M00004093D:B12 5325 1 1 0 1 0 1 M00004105C:A04 7221 0 0 0 0 0 0 M00004108A:E06 4937 0 0 0 0 0 0 M00004111D:A08 6874 0 0 1 0 0 0 M00004114C:F11 13183 0 0 0 0 0 0 M00004138B:H02 13272 0 0 0 0 0 0 M00004146C:C11 5257 0 1 0 0 0 0 M00004151D:B08 16977 0 0 0 0 0 0 M00004157C:A09 6455 0 0 0 0 0 0 M00004169C:C12 5319 0 0 0 0 0 0 M00004171D:B03 4908 0 0 0 0 0 0 M00004172C:D08 11494 0 0 0 0 0 0 M00004183C:D07 16392 0 0 0 0 0 0 M00004185C:C03 11443 0 0 0 0 0 0 M00004197D:H01 8210 0 0 0 0 0 0 M00004203B:C12 14311 0 0 0 0 0 0 M00004212B:C07 2379 0 0 0 0 0 0 M00004214C:H05 11451 0 0 0 0 0 0 M00004223A:G10 16918 0 0 0 0 0 0 M00004223B:D09 7899 0 0 0 0 0 0 M00004223D:E04 12971 0 0 0 0 0 0 M00004229B:F08 6455 0 0 0 0 0 0 M00004230B:C07 7212 0 0 0 0 0 0 M00004269D:D06 4905 0 0 0 0 0 0 M00004275C:C11 16914 0 0 0 0 0 0 M00004283B:A04 14286 0 0 0 0 0 0 M00004285B:E08 56020 0 0 0 0 0 0 M00004295D:F12 16921 0 0 0 0 0 0 M00004296C:H07 13046 0 0 0 0 0 0 M00004307C:A06 9457 0 0 0 0 0 0 M00004312A:G03 26295 0 0 0 0 0 0 M00004318C:D10 21847 0 0 0 0 0 0 M00004372A:A03 2030 0 0 0 0 0 0 M00004377C:F05 2102 0 0 0 0 0 0

TABLE 7 Clones in Clones in Clones in Clone Name Cluster ID Lib12 Lib13 Lib14 M00001340B:A06 17062 0 0 0 M00001340D:F10 11589 0 0 0 M00001341A:E12 4443 4 2 0 M00001342B:E06 39805 0 0 0 M00001343C:F10 2790 0 0 0 M00001343D:H07 23255 0 0 0 M00001345A:E01 6420 0 0 0 M00001346A:F09 5007 0 0 0 M00001346D:E03 6806 0 1 1 M00001346D:G06 5779 0 0 0 M00001346D:G06 5779 0 0 0 M00001347A:B10 13576 0 0 0 M00001348B:B04 16927 0 0 0 M00001348B:G06 16985 0 0 0 M00001349B:B08 3584 0 0 0 M00001350A:H01 7187 0 0 0 M00001351B:A08 3162 0 0 1 M00001351B:A08 3162 0 0 1 M00001352A:E02 16245 0 0 0 M00001353A:G12 8078 0 0 0 M00001353D:D10 14929 0 1 0 M00001355B:G10 14391 0 0 0 M00001357D:D11 4059 0 0 0 M00001361A:A05 4141 1 2 1 M00001361D:F08 2379 0 0 0 M00001362B:D10 5622 0 2 1 M00001362C:H11 945 0 0 0 M00001365C:C10 40132 0 0 0 M00001370A:C09 6867 0 0 0 M00001371C:E09 7172 0 0 1 M00001376B:G06 17732 2 0 0 M00001378B:B02 39833 0 0 0 M00001379A:A05 1334 0 0 0 M00001380D:B09 39886 0 0 0 M00001382C:A02 22979 1 0 0 M00001383A:C03 39648 0 0 0 M00001383A:C03 39648 0 0 0 M00001386C:B12 5178 0 0 0 M00001387A:C05 2464 0 0 0 M00001387B:G03 7587 0 0 0 M00001388D:G05 5832 0 0 0 M00001389A:C08 16269 2 0 0 M00001394A:F01 6583 0 0 0 M00001395A:C03 4016 0 0 0 M00001396A:C03 4009 2 0 0 M00001402A:E08 39563 0 0 0 M00001407B:D11 5556 0 0 0 M00001409C:D12 9577 0 0 0 M00001410A:D07 7005 0 0 0 M00001412B:B10 8551 0 0 0 M00001415A:H06 13538 0 0 0 M00001416A:H01 7674 0 0 0 M00001416B:H11 8847 1 0 0 M00001417A:E02 36393 0 0 0 M00001418B:F03 9952 0 0 0 M00001418D:B06 8526 0 0 0 M00001421C:F01 9577 0 0 0 M00001423B:E07 15066 0 0 0 M00001424B:G09 10470 0 0 0 M00001425B:H08 22195 0 0 0 M00001426D:C08 4261 0 0 0 M00001428A:H10 84182 0 0 0 M00001429A:H04 2797 0 0 0 M00001429B:A11 4635 0 0 0 M00001429D:D07 40392 0 0 0 M00001439C:F08 40054 0 0 0 M00001442C:D07 16731 0 0 0 M00001445A:F05 13532 0 0 0 M00001446A:F05 7801 0 1 0 M00001447A:G03 10717 0 0 0 M00001448D:C09 8 7 6 9 M00001448D:H01 36313 1 0 0 M00001449A:A12 5857 0 0 0 M00001449A:B12 41633 0 0 0 M00001449A:D12 3681 1 0 0 M00001449A:G10 36535 0 0 0 M00001449C:D06 86110 0 0 0 M00001450A:A02 39304 0 1 0 M00001450A:A11 32663 0 0 0 M00001450A:B12 82498 0 0 0 M00001450A:D08 27250 0 0 0 M00001452A:B04 84328 0 0 0 M00001452A:B12 86859 0 0 0 M00001452A:D08 1120 0 0 0 M00001452A:F05 85064 0 0 0 M00001452C:B06 16970 1 0 0 M00001453A:E11 16130 0 0 0 M00001453C:F06 16653 0 0 0 M00001454A:A09 83103 0 0 0 M00001454B:C12 7005 0 0 0 M00001454D:G03 689 0 0 1 M00001455A:E09 13238 0 0 0 M00001455B:E12 13072 0 0 0 M00001455D:F09 9283 0 0 0 M00001455D:F09 9283 0 0 0 M00001460A:F06 2448 0 0 0 M00001460A:F12 39498 0 0 0 M00001461A:D06 1531 0 0 1 M00001463C:B11 19 17 32 31 M00001465A:B11 10145 0 0 0 M00001466A:E07 4275 0 0 0 M00001467A:B07 38759 0 0 0 M00001467A:D04 39508 0 0 0 M00001467A:D08 16283 0 0 0 M00001467A:D08 16283 0 0 0 M00001467A:E10 39442 0 0 0 M00001468A:F05 7589 0 0 0 M00001469A:C10 12081 0 0 0 M00001469A:H12 19105 0 0 0 M00001470A:B10 1037 0 0 0 M00001470A:C04 39425 0 0 0 M00001471A:B01 39478 0 0 0 M00001481D:A05 7985 0 0 0 M00001490B:C04 18699 0 0 0 M00001494D:F06 7206 0 0 0 M00001497A:G02 2623 1 0 0 M00001499B:A11 10539 0 1 0 M00001500A:C05 5336 0 0 0 M00001500A:E11 2623 1 0 0 M00001500C:E04 9443 0 0 0 M00001501D:C02 9685 0 0 0 M00001504C:A07 10185 0 0 0 M00001504C:H06 6974 0 0 0 M00001504D:G06 6420 0 0 0 M00001507A:H05 39168 0 0 0 M00001511A:H06 39412 0 0 0 M00001512A:A09 39186 0 0 0 M00001512D:G09 3956 0 0 0 M00001513A:B06 4568 0 0 0 M00001513C:E08 14364 0 0 0 M00001514C:D11 40044 0 0 0 M00001517A:B07 4313 0 0 0 M00001518C:B11 8952 0 0 0 M00001528A:C04 7337 1 2 2 M00001528A:F09 18957 0 0 0 M00001528B:H04 8358 0 0 0 M00001531A:D01 38085 0 0 0 M00001532B:A06 3990 0 0 0 M00001533A:C11 2428 0 0 0 M00001534A:C04 16921 0 0 0 M00001534A:D09 5097 0 0 0 M00001534A:F09 5321 4 7 6 M00001534C:A01 4119 0 0 0 M00001535A:B01 7665 0 2 4 M00001535A:C06 20212 0 0 0 M00001535A:F10 39423 0 0 0 M00001536A:B07 2696 0 0 0 M00001536A:C08 39392 0 0 0 M00001537A:F12 39420 0 0 0 M00001537B:G07 3389 0 0 0 M00001540A:D06 8286 0 0 0 M00001541A:D02 3765 0 0 0 M00001541A:F07 22085 0 0 0 M00001541A:H03 39174 0 0 0 M00001542A:A09 22113 0 0 0 M00001542A:E06 39453 0 0 0 M00001544A:E03 12170 0 0 0 M00001544A:G02 19829 0 0 0 M00001544B:B07 6974 0 0 0 M00001545A:C03 19255 0 0 0 M00001545A:D08 13864 0 0 0 M00001546A:G11 1267 0 0 0 M00001548A:E10 5892 0 1 0 M00001548A:H09 1058 1 3 0 M00001549A:B02 4015 0 1 0 M00001549A:D08 10944 1 0 0 M00001549B:F06 4193 0 0 0 M00001549C:E06 16347 0 0 0 M00001550A:A03 7239 0 1 0 M00001550A:G01 5175 1 0 0 M00001551A:B10 6268 0 0 1 M00001551A:F05 39180 0 0 0 M00001551A:G06 22390 0 0 1 M00001551C:G09 3266 0 0 0 M00001552A:B12 307 6 11 4 M00001552A:D11 39458 0 0 0 M00001552B:D04 5708 0 0 0 M00001553A:H06 8298 0 0 0 M00001553B:F12 4573 0 0 0 M00001553D:D10 22814 0 0 0 M00001555A:B02 39539 0 0 0 M00001555A:C01 39195 0 0 0 M00001555D:G10 4561 0 0 0 M00001556A:C09 9244 0 1 0 M00001556A:F11 1577 0 0 2 M00001556A:H01 15855 1 1 0 M00001556B:C08 4386 3 0 1 M00001556B:G02 11294 0 0 0 M00001557A:D02 7065 0 0 0 M00001557A:D02 7065 0 0 0 M00001557A:F01 9635 0 0 0 M00001557A:F03 39490 0 0 0 M00001557B:H10 5192 0 0 0 M00001557D:D09 8761 0 0 0 M00001558B:H11 7514 0 0 0 M00001560D:F10 6558 0 0 0 M00001561A:C05 39486 0 0 0 M00001563B:F06 102 2 1 2 M00001564A:B12 5053 0 0 0 M00001571C:H06 5749 0 0 0 M00001578B:E04 23001 0 0 0 M00001579D:C03 6539 0 0 0 M00001583D:A10 6293 0 0 0 M00001586C:C05 4623 0 0 0 M00001587A:B11 39380 0 0 0 M00001594B:H04 260 1 0 0 M00001597C:H02 4837 1 0 0 M00001597D:C05 10470 0 0 0 M00001598A:G03 16999 4 2 6 M00001601A:D08 22794 0 0 0 M00001604A:B10 1399 6 3 3 M00001604A:F05 39391 0 0 0 M00001607A:E11 11465 0 0 0 M00001608A:B03 7802 0 0 0 M00001608B:E03 22155 0 0 0 M00001614C:F10 13157 0 0 0 M00001617C:E02 17004 0 0 0 M00001619C:F12 40314 0 0 0 M00001621C:C08 40044 0 0 0 M00001623D:F10 13913 0 0 0 M00001624A:B06 3277 0 0 0 M00001624C:F01 4309 0 0 0 M00001630B:H09 5214 0 1 2 M00001644C:B07 39171 0 0 0 M00001645A:C12 19267 0 0 0 M00001648C:A01 4665 0 0 0 M00001657D:C03 23201 0 0 0 M00001657D:F08 76760 0 0 0 M00001662C:A09 23218 0 0 0 M00001663A:E04 35702 0 0 0 M00001669B:F02 6468 0 0 0 M00001670C:H02 14367 0 0 0 M00001673C:H02 7015 0 0 0 M00001675A:C09 8773 0 0 0 M00001676B:F05 11460 2 0 0 M00001677C:E10 14627 0 0 0 M00001677D:A07 7570 0 0 0 M00001678D:F12 4416 1 2 0 M00001679A:A06 6660 0 0 0 M00001679A:F10 26875 0 0 0 M00001679B:F01 6298 0 0 0 M00001679C:F01 78091 0 0 0 M00001679D:D03 10751 0 0 0 M00001679D:D03 10751 0 0 0 M00001680D:F08 10539 0 1 0 M00001682C:B12 17055 0 0 0 M00001686A:E06 4622 0 0 0 M00001688C:F09 5382 0 0 0 M00001693C:G01 4393 0 0 0 M00001716D:H05 67252 0 0 0 M00003741D:C09 40108 0 0 0 M00003747D:C05 11476 0 0 0 M00003759B:B09 697 0 0 0 M00003762C:B08 17076 0 0 0 M00003763A:F06 3108 0 0 0 M00003774C:A03 67907 0 0 0 M00003796C:D05 5619 0 1 0 M00003826B:A06 11350 0 0 0 M00003833A:E05 21877 0 0 0 M00003837D:A01 7899 0 0 0 M00003839A:D08 7798 0 0 0 M00003844C:B11 6539 0 0 0 M00003846B:D06 6874 0 0 0 M00003851B:D10 13595 0 0 0 M00003853A:D04 5619 0 1 0 M00003853A:F12 10515 0 0 1 M00003856B:C02 4622 0 0 0 M00003857A:G10 3389 0 0 0 M00003857A:H03 4718 0 0 0 M00003871C:E02 4573 0 0 0 M00003875B:F04 12977 0 0 0 M00003875B:F04 12977 0 0 0 M00003875C:G07 8479 1 0 0 M00003876D:E12 7798 0 0 0 M00003879B:C11 5345 4 8 3 M00003879B:D10 31587 0 0 0 M00003879D:A02 14507 0 0 0 M00003885C:A02 13576 0 0 0 M00003885C:A02 13576 0 0 0 M00003906C:E10 9285 0 0 0 M00003907D:A09 39809 0 0 0 M00003907D:H04 16317 0 0 0 M00003909D:C03 8672 0 0 0 M00003912B:D01 12532 0 0 0 M00003914C:F05 3900 0 1 0 M00003922A:E06 23255 0 0 0 M00003958A:H02 18957 0 0 0 M00003958A:H02 18957 0 0 0 M00003958C:G10 40455 0 0 0 M00003958C:G10 40455 0 0 0 M00003968B:F06 24488 0 0 0 M00003970C:B09 40122 0 0 0 M00003974D:E07 23210 0 0 0 M00003974D:H02 23358 0 0 0 M00003975A:G11 12439 0 0 0 M00003978B:G05 5693 0 0 0 M00003981A:E10 3430 0 0 0 M00003982C:C02 2433 2 4 0 M00003983A:A05 9105 0 0 0 M00004028D:A06 6124 0 0 0 M00004028D:C05 40073 0 1 0 M00004031A:A12 9061 0 0 0 M00004031A:A12 9061 0 0 0 M00004035C:A07 37285 0 0 0 M00004035D:B06 17036 0 0 0 M00004059A:D06 5417 0 0 0 M00004068B:A01 3706 0 0 0 M00004072B:B05 17036 0 0 0 M00004081C:D10 15069 0 0 0 M00004081C:D12 14391 0 0 0 M00004086D:G06 9285 0 0 0 M00004087D:A01 6880 0 0 0 M00004093D:B12 5325 0 0 0 M00004093D:B12 5325 0 0 0 M00004105C:A04 7221 0 0 0 M00004108A:E06 4937 0 0 0 M00004111D:A08 6874 0 0 0 M00004114C:F11 13183 0 0 0 M00004138B:H02 13272 0 0 0 M00004146C:C11 5257 0 0 1 M00004151D:B08 16977 0 0 0 M00004157C:A09 6455 0 0 0 M00004169C:C12 5319 0 0 0 M00004171D:B03 4908 0 0 0 M00004172C:D08 11494 0 0 0 M00004183C:D07 16392 0 0 0 M00004185C:C03 11443 2 0 0 M00004197D:H01 8210 0 0 0 M00004203B:C12 14311 0 0 0 M00004212B:C07 2379 0 0 0 M00004214C:H05 11451 0 0 0 M00004223A:G10 16918 0 0 0 M00004223B:D09 7899 0 0 0 M00004223D:E04 12971 0 0 0 M00004229B:F08 6455 0 0 0 M00004230B:C07 7212 0 0 1 M00004269D:D06 4905 0 0 0 M00004275C:C11 16914 0 0 0 M00004283B:A04 14286 0 0 0 M00004285B:E08 56020 0 0 0 M00004295D:F12 16921 0 0 0 M00004296C:H07 13046 0 0 0 M00004307C:A06 9457 1 0 0 M00004312A:G03 26295 0 0 0 M00004318C:D10 21847 0 0 0 M00004372A:A03 2030 0 0 0 M00004377C:F05 2102 0 0 0

Example 5 Polynucleotides Differentially Expressed in High Metastatic Potential Breast Cancer Cells Versus Low Metastatic Breast Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential breast cancer tissue and low metastatic breast cancer cells. Expression of these sequences in breast cancer can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides with differential expression between high metastatic potential breast cancer cells and low metastatic potential breast cancer cells.

TABLE 8 Differentially expressed polynucleotides: High metastatic potential breast cancer vs. low metastatic breast cancer cells Clones in SEQ Cluster Clones in 2^(nd) ID NO. Differential Expression ID 1^(st)Library Library Ratio 9 High Breast > Low Breast (Lib3 > Lib4) 2623 31 4 7.561356 42 High Breast > Low Breast (Lib3 > Lib4) 307 196 75 2.549721 52 High Breast > Low Breast (Lib3 > Lib4) 19 1364 525 2.534854 62 High Breast > Low Breast (Lib3 > Lib4) 2623 31 4 7.561356 65 High Breast > Low Breast (Lib3 > Lib4) 5749 9 0 8.780930 66 High Breast > Low Breast (Lib3 > Lib4) 6455 6 0 5.853953 68 High Breast > Low Breast (Lib3 > Lib4) 6455 6 0 5.853953 114 High Breast > Low Breast (Lib3 > Lib4) 2030 32 4 7.805271 123 High Breast > Low Breast (Lib3 > Lib4) 3389 13 2 6.341782 144 High Breast > Low Breast (Lib3 > Lib4) 4623 12 2 5.853953 172 High Breast > Low Breast (Lib3 > Lib4) 102 278 116 2.338217 178 High Breast > Low Breast (Lib3 > Lib4) 3681 10 1 9.756589 214 High Breast > Low Breast (Lib3 > Lib4) 3900 8 1 7.805271 219 High Breast > Low Breast (Lib3 > Lib4) 3389 13 2 6.341782 223 High Breast > Low Breast (Lib3 > Lib4) 1399 19 7 2.648217 258 High Breast > Low Breast (Lib3 > Lib4) 4837 10 0 9.756589 317 High Breast > Low Breast (Lib3 > Lib4) 1577 25 3 8.130490 379 High Breast > Low Breast (Lib3 > Lib4) 260 27 2 13.17139 4 Low Breast > High Breast (Lib4 > Lib3) 3706 22 4 5.637215 39 Low Breast > High Breast (Lib4 > Lib3) 4016 6 0 6.149690 74 Low Breast > High Breast (Lib4 > Lib3) 6268 18 3 6.149690 81 Low Breast > High Breast (Lib4 > Lib3) 40392 8 1 8.199586 130 Low Breast > High Breast (Lib4 > Lib3) 13183 7 0 7.174638 157 Low Breast > High Breast (Lib4 > Lib3) 5417 9 0 9.224535 162 Low Breast > High Breast (Lib4 > Lib3) 9685 7 0 7.174638 183 Low Breast > High Breast (Lib4 > Lib3) 7337 16 3 5.466391 202 Low Breast > High Breast (Lib4 > Lib3) 6124 9 1 9.224535 298 Low Breast > High Breast (Lib4 > Lib3) 1037 22 4 5.637215 338 Low Breast > High Breast (Lib4 > Lib3) 689 36 17 2.170478 384 Low Breast > High Breast (Lib4 > Lib3) 697 72 30 2.459876 386 Low Breast > High Breast (Lib4 > Lib3) 4568 9 0 9.224535 388 Low Breast > High Breast (Lib4 > Lib3) 5622 13 2 6.662164

Example 6 Polynucleotides Differentially Expressed in High Metastatic Potential Lung Cancer Cells Versus Low Metastatic Lung Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential lung cancer tissue and low metastatic lung cancer cells. Expression of these sequences in lung cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells are associated can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides with differential expression between high metastatic potential lung cancer cells and low metastatic potential lung cancer cells:

TABLE 9 Differentially expressed polynucleotides: High metastatic potential lung cancer vs. low metastatic lung cancer cells Clones in SEQ Cluster Clones in 2^(nd) ID NO. Differential Expression ID 1^(st) Library Library Ratio 400 High Lung > Low Lung (Lib8 > Lib 9) 14929 23 16 2.008868 9 High Lung > Low Lung (Lib8 > Lib9) 2623 6 1 8.384840 34 High Lung > Low Lung (Lib8 > Lib9) 5832 5 0 6.987366 42 High Lung > Low Lung (Lib8 > Lib9) 307 79 27 4.088903 62 High Lung > Low Lung (Lib8 > Lib9) 2623 6 1 8.384840 74 High Lung > Low Lung (Lib8 > Lib9) 6268 5 0 6.987366 106 High Lung > Low Lung (Lib8 > Lib9) 10717 8 0 11.17978 119 High Lung > Low Lung (Lib8 > Lib9) 8 1355 122 15.52111 361 High Lung > Low Lung (Lib8 > Lib9) 1120 5 0 6.987366 369 High Lung > Low Lung (Lib8 > Lib9) 2790 6 0 8.384840 371 High Lung > Low Lung (Lib8 > Lib9) 8847 6 1 8.384840 379 High Lung > Low Lung (Lib8 > Lib9) 260 15 0 20.96210 395 High Lung > Low Lung (Lib8 > Lib9) 13538 9 1 12.57726 135 Low Lung > High Lung (Lib9 > Lib8) 36313 30 1 21.46731 154 Low Lung > High Lung (Lib9 > Lib8) 5345 27 6 3.220097 160 Low Lung > High Lung (Lib9 > Lib8) 4386 21 3 5.009039 260 Low Lung > High Lung (Lib9 > Lib8) 4141 27 4 4.830145 308 Low Lung > High Lung (Lib9 > Lib8) 15855 213 12 12.70149 323 Low Lung > High Lung (Lib9 > Lib8) 5257 25 5 3.577885 349 Low Lung > High Lung (Lib9 > Lib8) 2797 14 1 10.01807 381 Low Lung > High Lung (Lib9 > Lib8) 2428 19 2 6.797982

Example 7 Polynucleotides Differentially Expressed in High Metastatic Potential Colon Cancer Cells Versus Low Metastatic Colon Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential colon cancer tissue and low metastatic colon cancer cells. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides with differential expression between high metastatic potential colon cancer cells and low metastatic potential colon cancer cells:

TABLE 10 Differentially expressed polynucleotides: High metastatic potential colon cancer vs. low metastatic colon cancer cells Clones in SEQ Cluster Clones in 2^(nd) ID NO. Differential Expression ID 1^(st) Library Library Ratio 1 High Colon > Low Colon (Lib1 > Lib2) 6660 7 0 6.489973 176 High Colon > Low Colon (Lib1 > Lib2) 3765 19 6 2.935940 241 High Colon > Low Colon (Lib1 > Lib2) 4275 11 2 5.099264 362 High Colon > Low Colon (Lib1 > Lib2) 6420 8 0 7.417112 374 High Colon > Low Colon (Lib1 > Lib2) 6420 8 0 7.417112 39 Low Colon > High Colon (Lib2 > Lib1) 4016 14 5 3.020043 97 Low Colon > High Colon (Lib2 > Lib1) 945 21 9 2.516702 134 Low Colon > High Colon (Lib2 > Lib1) 2464 19 5 4.098630 317 Low Colon > High Colon (Lib2 > Lib1) 1577 40 12 3.595289 357 Low Colon > High Colon (Lib2 > Lib1) 4309 13 4 3.505407

Example 8 Polynucleotides Differentially Expressed at Higher Levels in High Metastatic Potential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential colon cancer tissue and normal tissue. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells are associated can be indicative of increased expression of genes or regulatory sequences involved in the advanced disease state which involves processes such as angiogenesis, dedifferentiation, cell replication, and metastasis. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides with differential expression between high metastatic potential colon cancer cells and normal colon cells:

TABLE 11 Differentially expressed polynucleotides: High metastatic potential colon tissue vs. normal colon tissue Clones Clones SEQ Cluster in 1^(st) in 2^(nd) ID NO. Differential Expression ID Library Library Ratio 52 High Colon Metastasis 19 10 0 11.69918 Tissue > Normal Colon Tissue of UC#3 (Lib20 > Lib18) 52 High Colon Metastasis 19 13 2 6.025646 Tissue > Normal Tissue in UC#2 (Lib17 > Lib15) 172 High Colon Metastasis 102 65 22 2.738930 Tissue > Normal Tissue in UC#2 (Lib17 > Lib15)

Example 9 Polynucleotides Differentially Expressed at Higher Levels in High Colon Tumor Potential Patient Tissue Versus Metastasized Colon Cancer Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high tumor potential colon cancer tissue and cells derived from high metastatic potential colon cancer cells. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the transformation of precancerous tissue to malignant tissue. This information can be useful in the prevention of achieving the advanced malignant state in these tissues, and can be important in risk assessment for a patient.

The following table summarizes identified polynucleotides with differential expression between high tumor potential colon cancer tissue and cells derived from high metastatic potential colon cancer cells:

TABLE 12 Differentially expressed polynucleotides: High tumor potential colon tissue vs. metastatic colon tissue Clones Clones SEQ Cluster in 1^(st) in 2^(nd) ID NO. Differential Expression ID Library Library Ratio 52 High Colon Tumor 19 69 10 5.160829 Tissue > Metastasis Tissue of UC#3 (Lib19 > Lib20) 119 High Colon Tumor 8 14 1 10.47124 Tissue > Metastasis Tissue of UC#3 (Lib19 > Lib20) 172 High Colon Tumor 102 43 10 3.216168 Tissue > Metastasis Tissue of UC#3 (Lib19 > Lib20)

Example 10 Polynucleotides Differentially Expressed at Higher Levels in High Tumor Potential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high tumor potential colon cancer tissue and normal tissue. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. For example, sequences that are highly expressed in the potential colon cancer cells are associated with or can be indicative of increased expression of genes or regulatory sequences involved in early tumor progression. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The following table summarizes identified polynucleotides with differential expression between high metastatic potential colon cancer cells and normal colon cells:

TABLE 13 Differentially expressed polynucleotides: High tumor potential colon tissue vs. normal colon tissue Clones Clones SEQ Cluster in 1^(st) in 2^(nd) ID NO. Differential Expression ID Library Library Ratio 52 High Colon Tumor 19 13 2 6.255508 Tissue > Normal Tissue of UC#2 (Lib16 > Lib15) 288 High Colon Tumor 1267 7 0 6.125253 Tissue > Normal Tissue of UC#2 (Lib16 > Lib15) 52 High Colon Tumor 19 69 0 60.37750 Tissue > Normal Tissue of UC#3 (Lib19 > Lib18) 119 High Colon Tumor 8 14 1 12.25050 Tissue > Normal Tissue of UC#3 (Lib19 > Lib18) 172 High Colon Tumor 102 43 7 5.375222 Tissue > Normal Tissue of UC#3 (Lib19 > Lib18)

Example 11 Polynucleotides Differentially Expressed Across Multiple Libraries

A number of polynucleotide sequences have been identified that are differentially expressed between cancerous cells and normal cells across all three tissue types tested (i.e., breast, colon, and lung). Expression of these sequences in a tissue or any origin can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. These polynucleotides can also serve as non-tissue specific markers of, for example, risk of metastasis of a tumor. The following table summarizes identified polynucleotides that were differentially expressed but without tissue type-specificity in the breast, colon, and lung libraries tested.

TABLE 14 Polynucleotides Differentially Expressed Across Multiple Library Comparisons Clones in Clones in SEQ Cluster 1^(st) 2^(nd) ID NO. Differential Expression ID Library Library Ratio 9 High Breast > Low Breast (Lib3 > Lib4) 2623 31 4 7.561356 High Lung > Low Lung (Lib8 > Lib9) 2623 6 1 8.384840 39 Low Breast > High Breast (Lib4 > Lib3) 4016 6 0 6.149690 Low Colon > High Colon (Lib2 > Lib1) 4016 14 5 3.020043 42 High Breast > Low Breast (Lib3 > Lib4) 307 196 75 2.549721 High Lung > Low Lung (Lib8 > Lib9) 307 79 27 4.088903 52 High Breast > Low Breast (Lib3 > Lib4) 19 1364 525 2.534854 High Colon Metastasis Tissue > Normal 19 10 0 11.69918 Colon Tissue of UC#3 (Lib20 > Lib18) High Colon Metastasis Tissue > Normal 19 13 2 6.025646 Tissue in UC#2 (Lib17 > Lib15) High Colon Tumor Tissue > Metastasis 19 69 10 5.160829 Tissue of UC#3 (Lib 19 > Lib20) High Colon Tumor Tissue > Normal 19 13 2 6.255508 Tissue of UC#2 (Lib16 > Lib15) High Colon Tumor Tissue > Normal 19 69 0 60.37750 Tissue of UC#3 (Lib19 > Lib18) 62 High Breast > Low Breast (Lib3 > Lib4) 2623 31 4 7.561356 High Lung > Low Lung (Lib8 > Lib9) 2623 6 1 8.384840 74 High Lung > Low Lung (Lib8 > Lib9) 6268 5 0 6.987366 Low Breast > High Breast (Lib4 > Lib3) 6268 18 3 6.149690 119 High Colon Tumor Tissue > Metastasis 8 14 1 10.47124 Tissue of UC#3 (Lib19 > Lib20) High Colon Tumor Tissue > Normal 8 14 1 12.25050 Tissue of UC#3 (Lib19 > Lib18) High Lung > Low Lung (Lib8 > Lib9) 8 1355 122 15.52111 172 High Breast > Low Breast (Lib3 > Lib4) 102 278 116 2.338217 High Colon Metastasis Tissue > Normal 102 65 22 2.738930 Tissue in UC#2 (Lib17 > Lib15) High Colon Tumor Tissue > Metastasis 102 43 10 3.216168 Tissue of UC#3 (Lib19 > Lib20) High Colon Tumor Tissue > Normal 102 43 7 5.375222 Tissue of UC#3 (Lib19 > Lib18) 317 High Breast > Low Breast (Lib3 > Lib4) 1577 25 3 8.130490 Low Colon > High Colon (Lib2 > Lib1) 1577 40 12 3.595289 379 High Breast > Low Breast (Lib3 > Lib4) 260 27 2 13.17139 High Lung > Low Lung (Lib8 > Lib9) 260 15 0 20.96210

Example 12 Polynucleotides Exhibiting Colon-Specific Expression

The cDNA libraries described herein were also analyzed to identify those polynucleotides that were specifically expressed in colon cells or tissue, i.e., the polynucleotides were identified in libraries prepared from colon cell lines or tissue, but not in libraries of breast or lung origin. The polynucleotides that were expressed in a colon cell line and/or in colon tissue, but were present in the breast or lung cDNA libraries described herein, are shown in Table 15.

TABLE 15 Polynucleotides specifically expressed in colon cells. Clones Clones SEQ ID in 1^(st) in 2^(nd) NO. Cluster Library Library 5 36535 2 0 13 27250 2 0 19 16283 3 0 24 16918 4 0 26 40108 2 0 32 32663 1 1 43 39833 2 0 47 18957 3 0 48 39508 2 0 56 7005 8 2 58 18957 3 0 59 18957 3 0 60 16283 3 0 64 13238 4 1 70 39442 2 0 71 17036 4 0 73 7005 8 2 83 11476 6 0 86 39425 2 0 94 21847 2 1 100 16731 3 1 101 12439 4 0 113 17055 4 0 120 67907 1 0 121 12081 4 0 124 39174 2 0 126 8210 2 6 128 40455 2 0 139 22195 3 0 143 86859 1 0 150 8672 4 4 153 16977 4 0 156 17036 4 0 159 40044 2 0 161 40044 2 0 163 22155 3 0 166 15066 4 0 170 11465 5 0 176 3765 19 6 181 86110 1 0 182 39648 2 0 185 17076 4 0 186 22794 2 0 187 39171 2 0 194 40455 2 0 199 16317 3 0 210 39186 2 0 211 40122 2 0 218 26295 2 0 222 4665 5 9 226 82498 1 0 227 35702 2 0 229 39648 2 0 231 85064 1 0 234 39391 2 0 236 39498 2 0 242 22113 3 0 247 19255 2 0 252 22814 3 0 253 39563 2 0 254 39420 2 0 257 39412 2 0 261 38085 2 0 265 40054 1 0 266 39423 2 0 267 39453 2 0 270 78091 1 0 276 39168 2 0 277 39458 2 0 278 14391 3 1 279 39195 2 0 282 12977 5 0 284 14391 3 1 290 16347 4 0 293 39478 2 0 294 39392 2 0 297 39180 2 0 299 6867 7 3 301 41633 1 1 302 23218 3 0 303 39380 2 0 309 84328 1 0 314 14367 3 0 320 39886 2 0 324 9061 5 2 327 16653 3 1 328 16985 4 0 329 12977 5 0 330 9061 5 2 333 16392 3 0 342 39486 2 0 344 6874 6 3 345 6874 6 3 353 11494 4 0 354 17062 3 0 355 16245 4 0 356 83103 1 0 358 13072 4 1 366 14364 1 0 368 84182 1 0 372 56020 1 0 89 7514 5 3 391 7570 5 3 393 23210 3 0

In addition to the above, SEQ ID NOS:159 and 161 were each present in one clone in each of Lib16 (Normal Colon Tumor Tissue), and SEQ ID NOS:344 and 345 were each present in one clone in Lib17 (High Colon Metastasis Tissue). No clones corresponding to the colon-specific polynucleotides in the table above were present in any of Libraries 3, 4, 8, or 9. The polynucleotide provided above can be used as markers of cells of colon origin, and find particular use in reference arrays, as described above.

Example 13 Identification of Contiguous Sequences Having a Polynucleotide of the Invention

The novel polynucleotides were used to screen publicly available and proprietary databases to determine if any of the polynucleotides of SEQ ID NOS:1-404 would facilitate identification of a contiguous sequence, e.g., the polynucleotides would provide sequence that would result in 5′ extension of another DNA sequence, resulting in production of a longer contiguous sequence composed of the provided polynucleotide and the other DNA sequence(s). Contiging was performed using the AssemblyLign program with the following parameters: 1) Overlap: Minimum Overlap Length: 30; % Stringency: 50; Minimum Repeat Length: 30; Alignment: gap creation penalty: 1.00, gap extension penalty: 1.00; 2) Consensus: % Base designation threshold: 80.

Using these parameters, 44 polynucleotides provided contiged sequences. These contiged sequences are provided as SEQ ID NOS:801-844. The contiged sequences can be correlated with the sequences of SEQ ID NOS:1-404 upon which the contiged sequences are based by identifying those sequences of SEQ ID NOS:1-404 and the contiged sequences of SEQ ID NOS:801-844 that share the same clone name in Table 1. It should be noted that of these 44 sequences that provided a contiged sequence, the following members of that group of 44 did not contig using the overlap settings indicated in parentheses (Stringency/Overlap): SEQ ID NO:804 (30%/10); SEQ ID NO:810 (20%/20); SEQ ID NO:812 (30%/10); SEQ ID NO:814 (40%/20); SEQ ID NO:816 (30%/10); SEQ ID NO:832 (30%/10); SEQ ID NO:840 (20%/20); SEQ ID NO:841 (40%/20). To generalize, the indicated polynucleotides did not contig using a minimum 20% stringency, 10 overlap. There was a corresponding increase in the number of degenerate codons in these sequences.

The contiged sequences (SEQ ID NO:801-844) thus represent longer sequences that encompass a polynucleotide sequence of the invention. The contiged sequences were then translated in all three reading frames to determine the best alignment with individual sequences using the BLAST programs as described above for SEQ ID NOS:1-404 and the validation sequences SEQ ID NOS:405-800. Again the sequences were masked using the XBLAST program for masking low complexity as described above in Example 1 (Table 2). Several of the contiged sequences were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 16). Thus the invention encompasses fragments, fusions, and variants of such polynucleotides that retain biological activity associated with the protein family and/or functional domain identified herein.

TABLE 16 Profile hits using contiged sequences SEQ ID Start NO. Sequence Name Profile (Stop) Score 809 Contig_RTA00000177AF.n.18.3.Seq_THC123051 ATPases  778 6040 (1612) 824 Contig_RTA00000187AF.g.24.1.Seq_THC168636 homeobox  531 12080  (707) 824 Contig_RTA00000187AF.g.24.1.Seq_THC168636 MAP kinase  769 5784 kinase (1494) 833 Contig_RTA00000190AF.j.4.1.Seq_THC228776 protein kinase  170 5027 (1010) 833 Contig_RTA00000190AF.j.4.1.Seq_THC228776 protein kinase  170 5027 (1010) All stop/start sequences are provided in the forward direction.

The profiles for the ATPases (AAA) and protein kinase families are described above in Example 2. The homeobox and MAP kinase kinase protein families are described further below.

Homeobox domain. The ‘homeobox’ is a protein domain of 60 amino acids (Gehring In: Guidebook to the Homeobox Genes, Duboule D., Ed., pp 1-10, Oxford University Press, Oxford, (1994); Buerglin In: Guidebook to the Homeobox Genes, pp 25-72, Oxford University Press, Oxford, (1994); Gehring Trends Biochem. Sci. (1992) 17:277-280; Gehring et al Annu. Rev. Genet. (1986) 20:147-173; Schofield Trends Neurosci. (1987) 10:3-6; see internet web site at copan.bioz.unibas.ch/homeo.html) first identified in number of Drosophila homeotic and segmentation proteins. It is extremely well conserved in many other animals, including vertebrates. This domain binds DNA through a helix-turn-helix type of structure. Several proteins that contain a homeobox domain play an important role in development. Most of these proteins are sequence-specific DNA-binding transcription factors. The homeobox domain is also very similar to a region of the yeast mating type proteins. These are sequence-specific DNA-binding proteins that act as master switches in yeast differentiation by controlling gene expression in a cell type-specific fashion.

A schematic representation of the homeobox domain is shown below. The helix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’ (for turn).

The pattern detects homeobox sequences 24 residues long and spans positions 34 to 57 of the homeobox domain.

MAP kinase kinase (MAPKK). MAP kinases (MAPK) are involved in signal transduction, and are important in cell cycle and cell growth controls. The MAP kinase kinases (MAPKK) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKK regulation studies have led to the discovery of at least four MAPKK convergent pathways in higher organisms. One of these is similar to the yeast pheromone response pathway which includes the ste11 protein kinase. Two other pathways require the activation of either one or both of the serine/threonine kinase-encoded oncogenes c-Raf-1 and c-Mos. Additionally, several studies suggest a possible effect of the cell cycle control regulator cyclin-dependent kinase 1 (cdc2) on MAPKK activity. Finally, MAPKKs are apparently essential transducers through which signals must pass before reaching the nucleus. For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishida et al., Trends Biochem Sci (1993) 18:128-31; Ruderman Curr Opin Cell Biol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55; Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal (1996) 8:533-44.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Deposit Information:

The following materials were deposited with the American Type Culture Collection: CMCC=(Chiron Master Culture Collection)

Cell Lines Deposited with ATCC Cell Line Deposit Date ATCC Accession No. CMCC Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377 CDNA Library Deposits Clone Name Cluster ID Sequence Name cDNA Library ES1 - ATCC# 207023 Deposit Date - Dec. 22, 1998 M00001395A:C03 4016 79.A1.sp6:130016.Seq M00001395A:C03 4016 RTA00000118A.c.4.1 M00001449A:D12 3681 RTA00000131A.g.15.2 M00001449A:D12 3681 79.E1.sp6:130064.Seq M00001452A:D08 1120 79.C2.sp6:130041.Seq M00001452A:D08 1120 RTA00000118A.p.15.3 M00001513A:B06 4568 79.D4.sp6:130055.Seq M00001513A:B06 4568 RTA00000122A.d.15.3 M00001517A:B07 4313 79.F4.sp6:130079.Seq M00001517A:B07 4313 RTA00000122A.n.3.1 M00001533A:C11 2428 RTA00000123A.1.21.1 M00001533A:C11 2428 79.A5.sp6:130020.Seq M00001533A:C11 2428 RTA00000123A.1.21.1.Seq_THC205063 M00001542A:A09 22113 79.F5.sp6:130080.Seq M00001542A:A09 22113 RTA00000125A.c.7.1 cDNA Library ES2 - ATCC# 207024 Deposit Date - Dec. 22, 1998 M00001343C:F10 2790 80.E1.sp6:130256.Seq M00001343C:F10 2790 RTA00000177AF.e.2.1.Seq_THC229461 M00001343C:F10 2790 RTA00000177AF.e.2.1 M00001343D:H07 23255 100.C1.sp6:131446.Seq M00001343D:H07 23255 RTA00000177AF.e.14.3.Seq_THC228776 M00001343D:H07 23255 80.F1.sp6:130268.Seq M00001343D:H07 23255 RTA00000177AF.e.14.3 M00001345A:E01 6420 172.E1.sp6:133925.Seq M00001345A:E01 6420 RTA00000177AF.f.10.3 M00001345A:E01 6420 RTA00000177AF.f.10.3.Seq_THC226443 M00001345A:E01 6420 80.G1.sp6:130280.Seq M00001347A:B10 13576 80.D2.sp6:130245.Seq M00001347A:B10 13576 100.E1.sp6:131470.Seq M00001347A:B10 13576 RTA00000177AF.g.16.1 M00001353A:G12 8078 80.E3.sp6:130258.Seq M00001353A:G12 8078 RTA00000177AR.l.13.1 M00001353A:G12 8078 172.C3.sp6:133903.Seq M00001353D:D10 14929 RTA00000177AF.m.1.2 M00001353D:D10 14929 80.F3.sp6:130270.Seq M00001353D:D10 14929 172.D3.sp6:133915.Seq M00001361A:A05 4141 80.B4.sp6:130223.Seq M00001361A:A05 4141 RTA00000177AF.p.20.3 M00001362B:D10 5622 80.D4.sp6:130247.Seq M00001362B:D10 5622 RTA00000178AF.a.11.1 cDNA Library ES3 - ATCC# 207025 Deposit Date - Dec. 22, 1998 M00001362C:H11 945 RTA00000178AR.a.20.1 M00001362C:H11 945 100.E4.sp6:131473.Seq M00001362C:H11 945 80.E4.sp6:130259.Seq M00001362C:H11 945 180.C2.sp6:135940.Seq M00001376B:G06 17732 RTA00000178AR.i.2.2 M00001376B:G06 17732 80.B5.sp6:130224.Seq M00001387A:C05 2464 80.D6.sp6:130249.Seq M00001387A:C05 2464 RTA00000178AF.n.18.1 M00001412B:B10 8551 RTA00000179AF.p.21.1 M00001412B:B10 8551 80.G7.sp6:130286.Seq M00001415A:H06 13538 80.B8.sp6:130227.Seq M00001415A:H06 13538 RTA00000180AF.a.24.1 M00001416B:H11 8847 80.C8.sp6:130239.Seq M00001416B:H11 8847 RTA00000180AF.b.16.1 M00001429D:D07 40392 RTA00000180AF.j.8.1 M00001429D:D07 40392 80.H9.sp6:130300.Seq M00001448D:H01 36313 80.A11.sp6:130218.Seq M00001448D:H01 36313 RTA00000181AF.e.23.1 cDNA Library ES4 - ATCC# 207026 Deposit Date - Dec. 22, 1998 M00001463C:B11 19 RTA00000182AF.b.7.1 M00001463C:B11 19 89.D1.sp6:130703.Seq M00001470A:B10 1037 89.F2.sp6:130728.Seq M00001470A:B10 1037 RTA00000121A.f.8.1 M00001497A:G02 2623 89.F3.sp6:130729.Seq M00001497A:G02 2623 RTA00000183AF.a.6.1 M00001500A:E11 2623 RTA00000183AF.b.14.1 M00001500A:E11 2623 89.A4.sp6:130670.Seq M00001501D:C02 9685 RTA00000183AF.c.11.1.Seq_THC109544 M00001501D:C02 9685 RTA00000183AF.c.11.1 M00001501D:C02 9685 89.C4.sp6:130694.Seq M00001504C:H06 6974 89.F4.sp6:130730.Seq M00001504C:H06 6974 RTA00000183AF.d.9.1 M00001504C:H06 6974 RTA00000183AF.d.9.1.Seq_THC223129 M00001504D:G06 6420 173.F5.SP6:134133.Seq M00001504D:G06 6420 89.G4.sp6:130742.Seq M00001504D:G06 6420 RTA00000183AF.d.11.1.Seq_THC226443 M00001504D:G06 6420 RTA00000183AF.d.11.1 M00001528A:C04 35555 89.B6.sp6:130684.Seq M00001528A:C04 7337 RTA00000123A.b.17.1 M00001528A:C04 35555 184.A5.sp6:135530.Seq cDNA Library ES5 - ATCC# 207027 Deposit Date - Dec. 22, 1998 M00001537B:G07 3389 RTA00000183AF.m.19.1 M00001537B:G07 3389 89.A8.sp6:130674.Seq M00001541A:D02 3765 89.C8.sp6:130698.Seq M00001541A:D02 3765 RTA00000135A.d.1.1 M00001544B:B07 6974 89.A9.sp6:130675.Seq M00001544B:B07 6974 RTA00000184AF.a.15.1 M00001546A:G11 1267 89.D9.sp6:130711.Seq M00001546A:G11 1267 RTA00000125A.o.5.1 M00001549B:F06 4193 89.G9.sp6:130747.Seq M00001549B:F06 4193 RTA00000184AF.e.13.1 M00001556A:F11 1577 173.C9.SP6:134101.Seq M00001556A:F11 1577 89.F11.sp6:130737.Seq M00001556A:F11 1577 RTA00000184AF.i.23.1 M00001556B:C08 4386 RTA00000184AF.j.4.1 M00001556B:C08 4386 89.H11.sp6:130761.Seq cDNA Library ES6 - ATCC# 207028 Deposit Date - Dec. 22, 1998 M00001563B:F06 102 RTA00000184AF.o.5.1 M00001563B:F06 102 90.B1.sp6:130871.Seq M00001571C:H06 5749 90.E1.sp6:130907.Seq M00001571C:H06 5749 RTA00000185AF.a.19.1 M00001594B:H04 260 90.D2.sp6:130896.Seq M00001594B:H04 260 RTA00000185AR.i.12.2 M00001597C:H02 4837 90.E2.sp6:130908.Seq M00001597C:H02 4837 RTA00000185AR.k.3.2 M00001624C:F01 4309 90.C4.sp6:130886.Seq M00001624C:F01 4309 RTA00000186AF.e.22.1 M00001679A:A06 6660 90.F6.sp6:130924.Seq M00001679A:A06 6660 122.B5.sp6:132089.Seq M00001679A:A06 6660 RTA00000187AF.h.15.1 M00003759B:B09 697 90.G8.sp6:130938.Seq M00003759B:B09 697 RTA00000188AF.d.6.1 M00003759B:B09 697 RTA00000188AF.d.6.1.Seq_THC178884 M00003844C:B11 6539 176.D9.sp6:134556.Seq M00003844C:B11 6539 RTA00000189AF.d.22.1 M00003844C:B11 6539 90.B10.sp6:130880.Seq M00003857A:G10 3389 90.A11.sp6:130869.Seq M00003857A:G10 3389 RTA00000189AF.g.3.1 cDNA Library ES7 - ATCC# 207029 Deposit Date - Dec. 22, 1998 M00003914C:F05 3900 99.E1.sp6:131278.Seq M00003914C:F05 3900 RTA00000190AF.g.13.1 M00003922A:E06 23255 RTA00000190AF.j.4.1 M00003922A:E06 23255 99.F1.sp6:131290.Seq M00003922A:E06 23255 RTA00000190AF.j.4.1.Seq_THC228776 M00003983A:A05 9105 99.C3.sp6:131256.Seq M00003983A:A05 9105 RTA00000191AF.a.21.2 M00004028D:A06 6124 RTA00000191AR.e.2.3 M00004028D:A06 6124 99.D3.sp6:131268.Seq M00004031A:A12 9061 RTA00000191AR.e.11.2 M00004031A:A12 9061 RTA00000191AR.e.11.3 M00004087D:A01 6880 RTA00000191AF.m.20.1 M00004087D:A01 6880 99.A5.sp6:131234.Seq M00004108A:E06 4937 99.E5.sp6:131282.Seq M00004108A:E06 4937 RTA00000191AF.p.21.1 M00004114C:F11 13183 123.D5.sp6:132305.Seq M00004114C:F11 13183 RTA00000192AF.a.24.1 M00004114C:F11 13183 99.G5.sp6:131306.Seq cDNA Library ES8 - ATCC# 207030 Deposit Date - Dec. 22, 1998 M00004146C:C11 5257 99.B6.sp6:131247.Seq M00004146C:C11 5257 177.F5.sp6:134768.Seq M00004146C:C11 5257 RTA00000192AF.f.3.1 M00004146C:C11 5257 RTA00000192AF.f.3.1.Seq_THC213833 M00004157C:A09 6455 RTA00000192AF.g.23.1 M00004157C:A09 6455 99.D6.sp6:131271.Seq M00004157C:A09 6455 123.E7.sp6:132319.Seq M00004172C:D08 11494 RTA00000192AF.j.6.1 M00004172C:D08 11494 99.G6.sp6:131307.Seq M00004172C:D08 11494 177.E6.sp6:134757.Seq M00004229B:F08 6455 RTA00000193AF.b.9.1 M00004229B:F08 6455 99.C8.sp6:131261.Seq cDNA Library ES9 - ATCC# 207031 Deposit Date - Dec. 22, 1998 M00001466A:E07 4275 RTA00000120A.j.14.1 M00001531A:H11 89.F6.sp6:130732.Seq M00001531A:H11 RTA00000123A.g.19.1 M00001551A:B10 6268 79.G9.sp6:130096.Seq M00001551A:B10 6268 184.C12.sp6:135561.Seq M00001551A:B10 6268 RTA00000126A.o.23.1 M00001552A:B12 307 RTA00000136A.o.4.2 M00001552A:B12 307 79.C7.sp6:130046.Seq M00001556A:H01 15855 RTA00000184AF.j.1.1 M00001586C:C05 4623 RTA00000185AF.f.4.1 M00001604A:B10 1399 79.G8.sp6:130095.Seq M00001604A:B10 1399 RTA00000129A.o.10.1 M00003879B:C11 5345 RTA00000189AF.1.19.1 M00003879B:C11 5345 90.B12.sp6:130882.Seq cDNA Library ES10 - ATCC#207032 Deposit Date - Dec. 22, 1998 M00001358C:C06 RTA00000177AF.o.4.3 M00001388D:G05 5832 80.F6.sp6:130273.Seq M00001388D:G05 5832 RTA00000178AF.o.23.1 M00001394A:F01 6583 RTA00000179AF.d.13.1 M00001394A:F01 6583 172.B8.sp6:133896.Seq M00001394A:F01 6583 80.H6.sp6:130297.Seq M00001429A:H04 2797 RTA00000180AF.i.19.1 M00001447A:G03 10717 RTA00000181AF.d.10.1 M00001448D:C09 8 80.H10.sp6:130301.Seq M00001448D:C09 8 RTA00000181AF.e.17.1 M00001448D:C09 8 100.B11.sp6:131444.Seq M00001454D:G03 689 RTA00000181AR.1.22.1 cDNA Library ES11 - ATCC#207033 Deposit Date - Dec. 22, 1998 M00003975A:G11 12439 RTA00000190AF.o.24.1 M00003978B:G05 5693 RTA00000190AF.p.17.2.Seq_THC173318 M00003978B:G05 5693 RTA00000190AF.p.17.2 M00004059A:D06 5417 RTA00000191AF.h.19.1 M00004068B:A01 3706 99.C4.sp6:131257.Seq M00004068B:A01 3706 RTA00000191AF.i.17.2 M00004205D:F06 99.E7.sp6:131284.Seq M00004205D:F06 177.G7.sp6:134782.Seq M00004205D:F06 RTA00000192AF.o.11.1 M00004212B:C07 2379 RTA00000192AF.p.8.1 M00004223A:G10 16918 RTA00000193AF.a.16.1 cDNA Library ES12 - ATCC# 207034 Deposit Date - Dec. 22, 1998 M00004223B:D09 7899 RTA00000193AF.a.17.1 M00004249D:G12 RTA00000193AF.c.22.1 M00004251C:G07 RTA00000193AF.d.2.1 M00004372A:A03 2030 RTA00000193AF.m.20.1 cDNA Library ES13 - ATCC#207035 Deposit Date - Dec. 22, 1998 M00001340B:A06 17062 80.A1.sp6:130208.Seq M00001340B:A06 17062 RTA00000177AF.b.8.4 M00001340D:F10 11589 80.B1.sp6:130220.Seq M00001340D:F10 11589 RTA00000177AF.b.17.4 M00001341A:E12 4443 80.C1.sp6:130232.Seq M00001341A:E12 4443 RTA00000177AF.b.20.4 M00001342B:E06 39805 80.D1.sp6:130244.Seq M00001342B:E06 39805 RTA00000177AF.c.21.3 M00001346A:F09 5007 RTA00000177AF.g.2.1 M00001346A:F09 5007 80.H1.sp6:130292.Seq M00001346D:G06 5779 RTA00000177AF.g.14.3 M00001346D:G06 5779 RTA00000177AF.g.14.1 M00001348B:B04 16927 80.E2.sp6:130257.Seq M00001348B:B04 16927 RTA00000177AF.h.9.3 M00001348B:G06 16985 RTA00000177AF.h.10.1 M00001348B:G06 16985 80.F2.sp6:130269.Seq M00001349B:B08 3584 RTA00000177AF.h.20.1 M00001349B:B08 3584 80.G2.sp6:130281.Seq M00001350A:H01 7187 100.C2.sp6:131447.Seq M00001350A:H01 7187 80.A3.sp6:130210.Seq M00001350A:H01 7187 RTA00000177AF.i.8.2 M00001352A:E02 16245 RTA00000177AF.k.9.3 M00001352A:E02 16245 172.D2.sp6:133914.Seq M00001352A:E02 16245 80.D3.sp6:130246.Seq M00001355B:G10 14391 RTA00000177AF.m.17.3 M00001355B:G10 14391 80.G3.sp6:130282.Seq M00001355B:G10 14391 172.H3.sp6:133963.Seq M00001355B:G10 14391 100.E3.sp6:131472.Seq M00001361D:F08 2379 80.C4.sp6:130235.Seq M00001361D:F08 2379 RTA00000178AF.a.6.1 M00001365C:C10 40132 RTA00000178AF.c.7.1 M00001365C:C10 40132 80.F4.sp6:130271.Seq M00001368D:E03 80.G4.sp6:130283.Seq M00001368D:E03 RTA00000178AF.d.20.1 M00001370A:C09 6867 80.H4.sp6:130295.Seq M00001370A:C09 6867 RTA00000178AF.e.12.1 M00001371C:E09 7172 100.A5.sp6:131426.Seq M00001371C:E09 7172 RTA00000178AF.f.9.1 M00001371C:E09 7172 80.A5.sp6:130212.Seq M00001378B:B02 39833 80.C5.sp6:130236.Seq M00001378B:B02 39833 RTA00000178AF.i.23.1 M00001379A:A05 1334 80.D5.sp6:130248.Seq M00001379A:A05 1334 RTA00000178AF.j.7.1 M00001380D:B09 39886 RTA00000178AF.j.24.1 M00001380D:B09 39886 80.E5.sp6:130260.Seq M00001381D:E06 80.F5.sp6:130272.Seq M00001381D:E06 RTA00000178AF.k.16.1 M00001382C:A02 22979 80.G5.sp6:130284.Seq M00001382C:A02 22979 RTA00000178AF.k.22.1 M00001384B:A11 80.B6.sp6:130225.Seq M00001384B:A11 RTA00000178AF.m.13.1 M00001386C:B12 5178 80.C6.sp6:130237.Seq M00001386C:B12 5178 RTA00000178AF.n.10.1 M00001387B:G03 7587 80.E6.sp6:130261.Seq M00001387B:G03 7587 RTA00000178AF.n.24.1 M00001389A:C08 16269 RTA00000178AF.p.1.1 M00001389A:C08 16269 80.G6.sp6:130285.Seq M00001396A:C03 4009 172.D8.sp6:133920.Seq M00001396A:C03 4009 80.A7.sp6:130214.Seq M00001396A:C03 4009 RTA00000179AF.e.20.1 M00001400B:H06 172.B9.sp6:133897.Seq M00001400B:H06 80.B7.sp6:130226.Seq M00001400B:H06 RTA00000179AF.j.13.1 M00001400B:H06 RTA00000179AF.j.13.1.Seq_THC105720 M00001402A:E08 39563 80.C7.sp6:130238.Seq M00001402A:E08 39563 RTA00000179AF.k.20.1 M00001407B:D11 5556 RTA00000179AF.n.10.1 M00001407B:D11 5556 80.D7.sp6:130250.Seq M00001410A:D07 7005 180.H5.sp6:136003.Seq M00001410A:D07 7005 RTA00000179AF.o.22.1 M00001410A:D07 7005 80.F7.sp6:130274.Seq M00001414A:B01 RTA00000180AF.a.9.1 M00001414A:B01 80.H7.sp6:130298.Seq M00001414C:A07 80.A8.sp6:130215.Seq M00001414C:A07 RTA00000180AF.a.11.1 M00001416A:H01 7674 79.C1.sp6:130040.Seq M00001416A:H01 7674 RTA00000118A.g.9.1 M00001417A:E02 36393 RTA00000180AF.c.2.1 M00001417A:E02 36393 80.D8.sp6:130251.Seq M00001423B:E07 15066 RTA00000180AF.e.24.1 M00001423B:E07 15066 80.H8.sp6:130299.Seq M00001424B:G09 10470 80.A9.sp6:130216.Seq M00001424B:G09 10470 RTA00000180AF.f.18.1 M00001425B:H08 22195 RTA00000180AF.g.7.1 M00001425B:H08 22195 80.B9.sp6:130228.Seq M00001426B:D12 RTA00000180AF.g.22.1 M00001426B:D12 80.C9.sp6:130240.Seq M00001426D:C08 4261 80.D9.sp6:130252.Seq M00001426D:C08 4261 RTA00000180AF.h.5.1 M00001428A:H10 84182 100.G9.sp6:131502.Seq M00001428A:H10 84182 RTA00000180AF.h.19.1 M00001428A:H10 84182 80.E9.sp6:130264.Seq M00001449A:A12 5857 80.B11.sp6:130230.Seq M00001449A:A12 5857 RTA00000118A.g.14.1 M00001449A:B12 41633 80.C11.sp6:130242.Seq M00001449A:B12 41633 RTA00000118A.g.16.1 M00001449A:G10 36535 RTA00000181AF.f.5.1 M00001449A:G10 36535 80.D11.sp6:130254.Seq M00001449A:G10 36535 100.D11.sp6:131468.Seq M00001449C:D06 86110 RTA00000181AF.f.12.1 M00001449C:D06 86110 80.E11.sp6:130266.Seq M00001450A:A02 39304 RTA00000118A.j.21.1.Seq_THC151859 M00001450A:A02 39304 RTA00000118A.j.21.1 M00001450A:A02 39304 79.F1.sp6:130076.Seq M00001450A:A02 39304 180.G9.sp6:135995.Seq M00001450A:A11 32663 80.F11.sp6:130278.Seq M00001450A:A11 32663 RTA00000118A.1.8.1 M00001450A:B12 82498 100.F11.sp6:131492.Seq M00001450A:B12 82498 RTA00000118A.m.10.1 M00001450A:B12 82498 79.G1.sp6:130088.Seq M00001450A:D08 27250 80.G11.sp6:130290.Seq M00001450A:D08 27250 180.B10.sp6:135936.Seq M00001450A:D08 27250 RTA00000181AF.g.10.1 M00001452A:B04 84328 RTA00000118A.p.10.1 M00001452A:B04 84328 79.A2.sp6:130017.Seq M00001452A:B12 86859 RTA00000118A.p.8.1 M00001452A:B12 86859 79.B2.sp6:130029.Seq M00001452A:F05 85064 RTA00000131A.m.23.1 M00001452A:F05 85064 79.D2.sp6:130053.Seq M00001452C:B06 16970 80.H11.sp6:130302.Seq M00001452C:B06 16970 100.C12.sp6:131457.Seq M00001452C:B06 16970 RTA00000181AR.i.18.2 M00001453A:E11 16130 80.A12.sp6:130219.Seq M00001453A:E11 16130 100.D12.sp6:131469.Seq M00001453A:E11 16130 RTA00000119A.c.13.1 M00001453C:F06 16653 80.B12.sp6:130231.Seq M00001453C:F06 16653 RTA00000181AF.k.5.3 M00001454A:A09 83103 RTA00000119A.e.24.2 M00001454A:A09 83103 79.G2.sp6:130089.Seq M00001454B:C12 7005 121.D1.sp6:131917.Seq M00001454B:C12 7005 RTA00000181AF.k.24.1 M00001454B:C12 7005 80.C12.sp6:130243.Seq M00001455B:E12 13072 80.F12.sp6:130279.Seq M00001455B:E12 13072 RTA00000181AR.m.5.2 M00001460A:F06 2448 89.A1.sp6:130667.Seq M00001460A:F06 2448 RTA00000119A.j.21.1 M00001461A:D06 1531 89.C1.sp6:130691.Seq M00001461A:D06 1531 RTA00000119A.o.3.1 M00001465A:B11 10145 79.F3.sp6:130078.Seq M00001465A:B11 10145 RTA00000120A.g.12.1 M00001467A:B07 38759 89.F1.sp6:130727.Seq M00001467A:B07 38759 RTA00000120A.m.12.3 M00001467A:D04 39508 RTA00000120A.o.2.1 M00001467A:D04 39508 89.G1.sp6:130739.Seq M00001467A:E10 39442 89.A2.sp6:130668.Seq M00001467A:E10 39442 RTA00000120A.o.21.1 M00001468A:F05 7589 RTA00000120A.p.23.1 M00001468A:F05 7589 89.B2.sp6:130680.Seq M00001469A:A01 RTA00000121A.c.10.1 M00001469A:A01 89.C2.sp6:130692.Seq M00001469A:C10 12081 89.D2.sp6:130704.Seq M00001469A:C10 12081 RTA00000133A.d.14.2 M00001469A:H12 19105 89.E2.sp6:130716.Seq M00001469A:H12 19105 RTA00000133A.e.15.1 M00001470A:C04 39425 89.G2.sp6:130740.Seq M00001470A:C04 39425 RTA00000133A.f.1.1 M00001471A:B01 39478 89.H2.sp6:130752.Seq M00001471A:B01 39478 RTA00000133A.i.5.1 M00001487B:H06 RTA00000182AF.1.15.1 M00001487B:H06 89.B3.sp6:130681.Seq M00001488B:F12 RTA00000182AF.l.20.1 M00001488B:F12 89.C3.sp6:130693.Seq M00001494D:F06 7206 RTA00000182AF.o.15.1 M00001494D:F06 7206 89.E3.sp6:130717.Seq M00001499B:A11 10539 RTA00000183AF.a.24.1 M00001499B:A11 10539 89.G3.sp6:130741.Seq M00001499B:A11 10539 173.B5.SP6:134085.Seq M00001500A:C05 5336 RTA00000183AF.b.13.1 M00001500A:C05 5336 89.H3.sp6:130753.Seq M00001504A:E01 RTA00000183AF.c.24.1 M00001504A:E01 89.D4.sp6:130706.Seq M00001504A:E01 RTA00000183AF.c.24.1.Seq_THC125912 M00001504C:A07 10185 RTA00000183AF.d.5.1 M00001504C:A07 10185 89.E4.sp6:130718.Seq M00001505C:C05 89.H4.sp6:130754.Seq M00001505C:C05 RTA00000183AF.e.1.1 M00001506D:A09 89.A5.sp6:130671.Seq M00001506D:A09 RTA00000183AF.e.23.1 M00001506D:A09 121.G6.sp6:131958.Seq M00001507A:H05 39168 RTA00000121A.l.10.1 M00001507A:H05 39168 89.B5.sp6:130683.Seq M00001535A:F10 39423 79.C5.sp6:130044.Seq M00001535A:F10 39423 RTA00000134A.k.22.1 M00001541A:H03 39174 79.E5.sp6:130068.Seq M00001541A:H03 39174 RTA00000124A.n.13.1 M00001544A:G02 19829 79.H5.sp6:130104.Seq M00001544A:G02 19829 RTA00000125A.h.24.4 M00001545A:D08 13864 RTA00000125A.m.9.1 M00001545A:D08 13864 79.B6.sp6:130033.Seq M00001551A:F05 39180 RTA00000126A.n.8.2 M00001551A:F05 39180 79.A7.sp6:130022.Seq M00001552A:D11 39458 RTA00000126A.p.15.2 M00001552A:D11 39458 79.D7.sp6:130058.Seq M00001557A:F03 39490 RTA00000128A.b.4.1 cDNA Library ES14 - ATCC# 207036 Deposit Date - Dec. 22, 1998 M00001511A:H06 39412 RTA00000133A.k.17.1 M00001511A:H06 39412 89.C5.sp6:130695.Seq M00001512A:A09 39186 89.D5.sp6:130707.Seq M00001512A:A09 39186 RTA00000121A.p.15.1 M00001512D:G09 3956 89.E5.sp6:130719.Seq M00001512D:G09 3956 173.H5.SP6:134157.Seq M00001512D:G09 3956 RTA00000183AF.g.3.1 M00001513B:G03 RTA00000183AF.g.9.1 M00001513B:G03 89.F5.sp6:130731.Seq M00001513B:G03 RTA00000183AF.g.9.1.Seq_THC198280 M00001513C:E08 14364 RTA00000183AF.g.12.1 M00001513C:E08 14364 89.G5.sp6:130743.Seq M00001514C:D11 40044 RTA00000183AF.g.22.1 M00001514C:D11 40044 RTA00000183AF.g.22.1.Seq_THC232899 M00001514C:D11 40044 89.H5.sp6:130755.Seq M00001518C:B11 8952 89.A6.sp6:130672.Seq M00001518C:B11 8952 RTA00000183AF.h.15.1 M00001528B:H04 8358 89.D6.sp6:130708.Seq M00001528B:H04 8358 RTA00000183AF.i.5.1 M00001531A:D01 38085 RTA00000123A.e.15.1 M00001531A:D01 38085 89.E6.sp6:130720.Seq M00001534A:C04 16921 RTA00000183AF.k.6.1 M00001534A:C04 16921 89.H6.sp6:130756.Seq M00001534A:D09 5097 RTA00000134A.k.1.1 M00001534A:D09 5097 RTA00000134A.k.1.1.Seq_THC215869 M00001534C:A01 4119 RTA00000183AF.k.16.1 M00001534C:A01 4119 89.C7.sp6:130697.Seq M00001535A:C06 20212 89.E7.sp6:130721.Seq M00001535A:C06 20212 RTA00000134A.1.22.1.Seq_THC128232 M00001535A:C06 20212 RTA00000134A.1.22.1 M00001536A:B07 2696 RTA00000134A.m.13.1 M00001536A:B07 2696 89.F7.sp6:130733.Seq M00001537A:F12 39420 89.H7.sp6:130757.Seq M00001537A:F12 39420 RTA00000134A.o.23.1 M00001540A:D06 8286 89.B8.sp6:130686.Seq M00001540A:D06 8286 RTA00000183AF.o.1.1 M00001542A:E06 39453 89.E8.sp6:130722.Seq M00001542A:E06 39453 RTA00000135A.g.11.1 M00001544A:E06 RTA00000184AF.a.8.1 M00001544A:E06 173.G7.SP6:134147.Seq M00001544A:E06 89.H8.sp6:130758.Seq M00001545A:B02 89.B9.sp6:130687.Seq M00001545A:B02 RTA00000135A.1.2.2 M00001548A:E10 5892 89.E9.sp6:130723.Seq M00001548A:E10 5892 RTA00000184AF.d.11.1 M00001548A:E10 5892 RTA00000184AF.d.11.1.Seq_THC161896 M00001549C:E06 16347 89.H9.sp6:130759.Seq M00001549C:E06 16347 RTA00000184AF.e.15.1 M00001550A:A03 7239 89.A10.sp6:130676.Seq M00001550A:A03 7239 RTA00000126A.m.4.2 M00001550A:G01 5175 RTA00000184AF.f.3.1 M00001550A:G01 5175 89.B10.sp6:130688.Seq M00001551A:G06 22390 RTA00000136A.j.13.1 M00001551A:G06 22390 89.C10.sp6:130700.Seq M00001551C:G09 3266 RTA00000184AR.g.1.1 M00001551C:G09 3266 89.D10.sp6:130712.Seq M00001553A:H06 8298 RTA00000127A.d.19.1 M00001553A:H06 8298 89.G10.sp6:130748.Seq M00001553B:F12 4573 89.H10.sp6:130760.Seq M00001553B:F12 4573 RTA00000184AF.h.9.1 M00001555A:B02 39539 RTA00000127A.i.21.1 M00001555A:B02 39539 89.B11.sp6:130689.Seq M00001555A:C01 39195 89.C11.sp6:130701.Seq M00001555A:C01 39195 RTA00000137A.c.16.1 M00001555D:G10 4561 RTA00000184AF.i.21.1 M00001555D:G10 4561 89.D11.sp6:130713.Seq M00001556A:C09 9244 89.E11.sp6:130725.Seq M00001556A:C09 9244 RTA00000127A.l.3.1 M00001556B:G02 11294 RTA00000184AF.j.6.1 M00001556B:G02 11294 89.A12.sp6:130678.Seq M00001557B:H10 5192 173.E9.SP6:134125.Seq M00001557B:H10 5192 RTA00000184AF.k.2.1 M00001557B:H10 5192 89.D12.sp6:130714.Seq M00001557D:D09 8761 RTA00000184AF.k.12.1 M00001557D:D09 8761 89.E12.sp6:130726.Seq M00001558B:H11 7514 RTA00000184AF.k.21.1 M00001558B:H11 7514 89.G12.sp6:130750.Seq M00001559B:F01 89.H12.sp6:130762.Seq M00001559B:F01 RTA00000184AF.l.11.1 M00001560D:F10 6558 90.A1.sp6:130859.Seq M00001560D:F10 6558 RTA00000184AF.m.21.1 M00001566B:D11 RTA00000184AF.p.3.1 M00001566B:D11 90.D1.sp6:130895.Seq M00001583D:A10 6293 RTA00000185AF.e.11.1 M00001583D:A10 6293 90.A2.sp6:130860.Seq M00001590B:F03 RTA00000185AF.g.11.1 M00001590B:F03 90.C2.sp6:130884.Seq M00001597D:C05 10470 RTA00000185AF.k.6.1 M00001597D:C05 10470 90.F2.sp6:130920.Seq M00001598A:G03 16999 90.G2.sp6:130932.Seq M00001598A:G03 16999 RTA00000185AF.k.9.1 M00001601A:D08 22794 RTA00000138A.b.5.1 M00001601A:D08 22794 90.H2.sp6:130944.Seq M00001607A:E11 11465 RTA00000185AF.m.19.1 M00001607A:E11 11465 90.A3.sp6:130861.Seq M00001608A:B03 7802 RTA00000185AF.n.5.1 M00001608A:B03 7802 90.B3.sp6:130873.Seq M00001608B:E03 22155 RTA00000185AF.n.9.1 M00001608B:E03 22155 90.C3.sp6:130885.Seq M00001608D:A11 RTA00000185AF.n.12.1 M00001608D:A11 90.D3.sp6:130897.Seq M00001614C:F10 13157 RTA00000186AF.a.6.1 M00001614C:F10 13157 90.E3.sp6:130909.Seq M00001617C:E02 17004 RTA00000186AF.b.21.1 M00001617C:E02 17004 90.F3.sp6:130921.Seq M00001619C:F12 40314 90.G3.sp6:130933.Seq M00001619C:F12 40314 RTA00000186AF.c.15.1 M00001621C:C08 40044 RTA00000186AF.d.1.1 M00001621C:C08 40044 RTA00000186AF.d.1.1.Seq_THC232899 M00001621C:C08 40044 90.H3.sp6:130945.Seq M00001621C:C08 40044 122.E1.sp6:132121.Seq M00001623D:F10 13913 RTA00000186AF.e.6.1 M00001623D:F10 13913 90.A4.sp6:130862.Seq M00001632D:H07 RTA00000186AF.h.14.1.Seq_THC112525 M00001632D:H07 RTA00000186AF.h.14.1 M00001632D:H07 90.E4.sp6:130910.Seq M00001632D:H07 176.A3.sp6:134514.Seq M00001644C:B07 39171 RTA00000186AF.l.7.1 M00001644C:B07 39171 90.F4.sp6:130922.Seq M00001644C:B07 39171 217.A12.sp6:139369.Seq M00001645A:C12 19267 RTA00000186AF.l.12.1.Seq_THC178183 M00001645A:C12 19267 176.G3.sp6:134586.Seq M00001645A:C12 19267 RTA00000186AF.l.12.1 M00001645A:C12 19267 90.G4.sp6:130934.Seq M00001648C:A01 4665 90.H4.sp6:130946.Seq M00001648C:A01 4665 RTA00000186AF.m.3.1 M00001657D:C03 23201 RTA00000187AF.a.14.1 M00001657D:C03 23201 90.B5.sp6:130875.Seq M00001657D:F08 76760 90.C5.sp6:130887.Seq M00001657D:F08 76760 RTA00000187AF.a.15.1 M00001662C:A09 23218 RTA00000187AR.c.5.2 M00001662C:A09 23218 90.D5.sp6:130899.Seq M00001663A:E04 35702 90.E5.sp6:130911.Seq M00001663A:E04 35702 RTA00000187AR.c.15.2 M00001669B:F02 6468 90.F5.sp6:130923.Seq M00001669B:F02 6468 RTA00000187AF.d.15.1 M00001670C:H02 14367 90.G5.sp6:130935.Seq M00001670C:H02 14367 RTA00000187AF.e.8.1 M00001673C:H02 7015 90.H5.sp6:130947.Seq M00001673C:H02 7015 RTA00000187AF.f.18.1 M00001675A:C09 8773 RTA00000187AF.f.24.1 M00001675A:C09 8773 90.A6.sp6:130864.Seq M00001675A:C09 8773 RTA00000187AF.f.24.1.Seq_THC220002 M00001676B:F05 11460 RTA00000187AF.g.12.1 M00001676B:F05 11460 90.B6.sp6:130876.Seq M00001676B:F05 11460 219.F2.sp6:139035.Seq M00001677D:A07 7570 90.D6.sp6:130900.Seq M00001677D:A07 7570 RTA00000187AF.g.24.1 M00001677D:A07 7570 RTA00000187AF.g.24.1.Seq_THC168636 M00001678D:F12 4416 90.E6.sp6:130912.Seq M00001678D:F12 4416 RTA00000187AF.h.13.1 M00001679A:F10 26875 RTA00000187AF.i.1.1 M00001679A:F10 26875 90.A7.sp6:130865.Seq M00001679B:F01 6298 90.B7.sp6:130877.Seq M00001679B:F01 6298 RTA00000187AR.i.10.2 M00001680D:F08 10539 90.F7.sp6:130925.Seq M00001680D:F08 10539 219.F6.sp6:139039.Seq M00001680D:F08 10539 RTA00000187AF.l.7.1 M00001682C:B12 17055 90.G7.sp6:130937.Seq M00001682C:B12 17055 RTA00000187AF.m.3.1 M00001682C:B12 17055 176.D6.sp6:134553.Seq M00001688C:F09 5382 90.A8.sp6:130866.Seq M00001688C:F09 5382 RTA00000187AF.m.23.2 M00001693C:G01 4393 RTA00000187AF.n.17.1 M00001693C:G01 4393 90.B8.sp6:130878.Seq M00001716D:H05 67252 RTA00000187AF.o.6.1 M00001716D:H05 67252 90.C8.sp6:130890.Seq M00003741D:C09 40108 90.D8.sp6:130902.Seq M00003741D:C09 40108 RTA00000187AF.o.24.1 M00003747D:C05 11476 RTA00000187AF.p.19.1 M00003747D:C05 11476 90.E8.sp6:130914.Seq M00003747D:C05 11476 RTA00000187AF.p.19.1.Seq_THC108482 M00003747D:C05 11476 219.H8.sp6:139065.Seq M00003754C:E09 90.F8.sp6:130926.Seq M00003754C:E09 RTA00000188AF.b.12.1 M00003761D:A09 RTA00000188AF.d.11.1 M00003761D:A09 90.H8.sp6:130950.Seq M00003761D:A09 RTA00000188AF.d.11.1.Seq_THC212094 M00003762C:B08 17076 RTA00000188AF.d.21.1.Seq_THC208760 M00003762C:B08 17076 90.A9.sp6:130867.Seq M00003762C:B08 17076 RTA00000188AF.d.21.1 M00003763A:F06 3108 RTA00000188AF.d.24.1 M00003763A:F06 3108 90.B9.sp6:130879.Seq M00003774C:A03 67907 RTA00000188AF.g.11.1.Seq_THC123222 M00003774C:A03 67907 RTA00000188AF.g.11.1 M00003774C:A03 67907 90.C9.sp6:130891.Seq M00003784D:D12 RTA00000188AF.i.8.1 M00003784D:D12 90.D9.sp6:130903.Seq M00003839A:D08 7798 RTA00000189AF.c.18.1 M00003839A:D08 7798 90.A10.sp6:130868.Seq M00003851B:D08 90.D10.sp6:130904.Seq M00003851B:D08 RTA00000189AF.f.7.1 M00003851B:D10 13595 90.E10.sp6:130916.Seq M00003851B:D10 13595 RTA00000189AF.f.8.1 M00003853A:D04 5619 90.F10.sp6:130928.Seq M00003853A:D04 5619 RTA00000189AF.f.17.1 M00003853A:F12 10515 90.G10.sp6:130940.Seq M00003853A:F12 10515 RTA00000189AF.f.18.1 M00003856B:C02 4622 90.H10.sp6:130952.Seq M00003856B:C02 4622 RTA00000189AF.g.1.1 M00003857A:H03 4718 90.B11.sp6:130881.Seq M00003857A:H03 4718 RTA00000189AF.g.5.1.Seq_THC196102 M00003857A:H03 4718 RTA00000189AF.g.5.1 cDNA Library ES15 - ATCC# 207037 Deposit Date - Dec. 22, 1998 M00003867A:D10 90.C11.sp6:130893.Seq M00003867A:D10 RTA00000189AF.h.17.1 M00003871C:E02 4573 RTA00000189AF.j.12.1 M00003875C:G07 8479 90.G11.sp6:130941.Seq M00003875C:G07 8479 RTA00000189AF.j.22.1 M00003875D:D11 90.H11.sp6:130953.Seq M00003875D:D11 RTA00000189AF.j.23.1 M00003876D:E12 7798 90.A12.sp6:130870.Seq M00003876D:E12 7798 RTA00000189AF.k.12.1 M00003906C:E10 9285 90.H12.sp6:130954.Seq M00003906C:E10 9285 RTA00000190AF.d.7.1 M00003907D:A09 39809 99.A1.sp6:131230.Seq M00003907D:A09 39809 RTA00000190AF.e.3.1.Seq_THC150217 M00003907D:A09 39809 RTA00000190AF.e.3.1 M00003907D:H04 16317 99.B1.sp6:131242.Seq M00003907D:H04 16317 RTA00000190AF.e.6.1 M00003909D:C03 8672 RTA00000190AF.f.11.1 M00003909D:C03 8672 99.C1.sp6:131254.Seq M00003968B:F06 24488 RTA00000190AF.n.16.1 M00003968B:F06 24488 99.C2.sp6:131255.Seq M00003970C:B09 40122 RTA00000190AF.n.23.1 M00003970C:B09 40122 RTA00000190AF.n.23.1.Seq_THC109227 M00003970C:B09 40122 99.D2.sp6:131267.Seq M00003974D:E07 23210 RTA00000190AF.o.20.1 M00003974D:E07 23210 RTA00000190AF.o.20.1.Seq_THC207240 M00003974D:E07 23210 99.E2.sp6:131279.Seq M00003974D:H02 23358 RTA00000190AF.o.21.1.Seq_THC207240 M00003974D:H02 23358 RTA00000190AF.o.21.1 M00003974D:H02 23358 99.F2.sp6:131291.Seq M00003981A:E10 3430 99.A3.sp6:131232.Seq M00003981A:E10 3430 RTA00000191AF.a.9.1 M00003982C:C02 2433 RTA00000191AF.a.15.2 M00003982C:C02 2433 99.B3.sp6:131244.Seq M00003982C:C02 2433 RTA00000191AF.a.15.2.Seq_THC79498 M00004028D:C05 40073 RTA00000191AF.e.3.1 M00004028D:C05 40073 99.E3.sp6:131280.Seq M00004035C:A07 37285 99.H3.sp6:131316.Seq M00004035C:A07 37285 RTA00000191AF.f.11.1 M00004035D:B06 17036 RTA00000191AF.f.13.1 M00004035D:B06 17036 99.A4.sp6:131233.Seq M00004072A:C03 RTA00000191AF.j.9.1 M00004072A:C03 99.D4.sp6:131269.Seq M00004081C:D10 15069 99.F4.sp6:131293.Seq M00004081C:D10 15069 RTA00000191AF.l.6.1 M00004086D:G06 9285 99.H4.sp6:131317.Seq M00004086D:G06 9285 RTA00000191AF.m.18.1 M00004105C:A04 7221 99.D5.sp6:131270.Seq M00004105C:A04 7221 RTA00000191AF.p.9.1 M00004171D:B03 4908 RTA00000192AF.j.2.1 M00004171D:B03 4908 99.F6.sp6:131295.Seq M00004185C:C03 11443 RTA00000192AF.l.13.2 M00004185C:C03 11443 123.A8.sp6:132272.Seq M00004185C:C03 11443 99.A7.sp6:131236.Seq M00004191D:B11 RTA00000192AF.m.12.1 M00004191D:B11 99.B7.sp6:131248.Seq M00004191D:B11 123.C8.sp6:132296.Seq M00004197D:H01 8210 99.C7.sp6:131260.Seq M00004197D:H01 8210 123.E8.sp6:132320.Seq M00004197D:H01 8210 RTA00000192AF.n.13.1 M00004203B:C12 14311 99.D7.sp6:131272.Seq M00004203B:C12 14311 RTA00000192AF.o.2.1 M00004214C:H05 11451 177.D8.sp6:134747.Seq M00004214C:H05 11451 RTA00000192AF.p.17.1 M00004223D:E04 12971 RTA00000193AF.a.20.1 M00004223D:E04 12971 99.B8.sp6:131249.Seq M00004269D:D06 4905 99.H8.sp6:131321.Seq M00004269D:D06 4905 RTA00000193AF.e.14.1 M00004295D:F12 16921 99.D9.sp6:131274.Seq M00004295D:F12 16921 RTA00000193AF.h.15.1 M00004296C:H07 13046 99.E9.sp6:131286.Seq M00004296C:H07 13046 RTA00000193AF.h.19.1 M00004307C:A06 9457 RTA00000193AF.i.14.2 M00004307C:A06 9457 99.F9.sp6:131298.Seq M00004307C:A06 9457 123.D11.sp6:132311.Seq M00004312A:G03 26295 RTA00000193AF.i.24.2 M00004312A:G03 26295 99.G9.sp6:131310.Seq M00004312A:G03 26295 RTA00000193AF.i.24.2.Seq_THC197345 M00004318C:D10 21847 RTA00000193AF.j.9.1 M00004318C:D10 21847 99.H9.sp6:131322.Seq M00004359B:G02 RTA00000193AF.m.5.1.Seq_THC173318 M00004359B:G02 RTA00000193AF.m.5.1 M00004505D:F08 RTA00000194AF.b.19.1 M00004505D:F08 99.H10.sp6:131323.Seq M00004692A:H08 99.B11.sp6:131252.Seq M00004692A:H08 RTA00000194AF.c.24.1 M00004692A:H08 377.F4.sp6:141957.Seq M00005180C:G03 RTA00000194AF.f.4.1 cDNA Library ES16 - ATCC#207038 Deposit Date - Dec. 22, 1998 M00001346D:E03 6806 RTA00000177AF.g.13.3 M00001350A:B08 80.H2.sp6:130293.Seq M00001350A:B08 RTA00000177AF.i.6.2 M00001357D:D11 4059 RTA00000177AF.n.18.3.Seq_THC123051 M00001357D:D11 4059 RTA00000177AF.n.18.3 M00001409C:D12 9577 RTA00000179AF.o.17.1 M00001409C:D12 9577 80.E7.sp6:130262.Seq M00001418B:F03 9952 RTA00000180AF.c.20.1 M00001418B:F03 9952 RTA00000180AF.c.20.1.Seq_THC162284 M00001418B:F03 9952 80.E8.sp6:130263.Seq M00001418D:B06 8526 RTA00000180AF.d.1.1 M00001421C:F01 9577 RTA00000180AF.d.23.1 M00001421C:F01 9577 80.G8.sp6:130287.Seq M00001429B:A11 4635 RTA00000180AF.i.20.1 M00001432C:F06 RTA00000180AF.k.24.1 M00001439C:F08 40054 RTA00000180AF.p.10.1 M00001442C:D07 16731 RTA00000181AF.a.20.1 M00001442C:D07 16731 80.C10.sp6:130241.Seq M00001443B:F01 80.D10.sp6:130253.Seq M00001443B:F01 RTA00000181AF.b.7.1 M00001445A:F05 13532 80.E10.sp6:130265.Seq M00001445A:F05 13532 RTA00000181AF.c.4.1 M00001446A:F05 7801 RTA00000181AF.c.21.1 M00001455A:E09 13238 RTA00000181AF.m.4.1 M00001455A:E09 13238 RTA00000181AF.m.4.1.Seq_THC140691 M00001460A:F12 39498 RTA00000119A.j.20.1 M00001481D:A05 7985 RTA00000182AR.j.2.1 M00001490B:C04 18699 RTA00000182AF.m.16.1 M00001490B:C04 18699 89.D3.sp6:130705.Seq M00001500C:E04 9443 89.B4.sp6:130682.Seq M00001500C:E04 9443 RTA00000183AF.c.1.1 M00001532B:A06 3990 89.G6.sp6:130744.Seq M00001532B:A06 3990 RTA00000183AF.j.11.1 M00001534A:F09 5321 89.B7.sp6:130685.Seq M00001534A:F09 5321 RTA00000183AF.k.8.1 M00001535A:B01 7665 RTA00000134A.l.19.1 M00001536A:C08 39392 89.G7.sp6:130745.Seq M00001536A:C08 39392 RTA00000134A.m.16.1 M00001541A:F07 22085 RTA00000135A.e.5.2 M00001542B:B01 RTA00000183AF.p.4.1 M00001542B:B01 89.F8.sp6:130734.Seq M00001544A:E03 12170 RTA00000125A.h.18.4 M00001545A:C03 19255 RTA00000135A.m.18.1 M00001545A:C03 19255 184.B10.sp6:135547.Seq M00001545A:C03 19255 89.C9.sp6:130699.Seq M00001548A:H09 1058 RTA00000126A.e.20.3.Seq_THC217534 M00001548A:H09 1058 RTA00000126A.e.20.3 M00001548A:H09 1058 79.F6.sp6:130081.Seq M00001549A:B02 4015 RTA00000136A.e.12.1 M00001549A:B02 4015 79.G6.sp6:130093.Seq M00001549A:D08 10944 RTA00000126A.h.17.2 M00001552B:D04 5708 RTA00000184AF.g.12.1 M00001552B:D04 5708 89.E10.sp6:130724.Seq M00001552D:A01 89.F10.sp6:130736.Seq M00001552D:A01 RTA00000184AF.g.22.1 M00001553D:D10 22814 RTA00000184AF.h.14.1 M00001553D:D10 22814 89.A11.sp6:130677.Seq M00001558A:H05 RTA00000128A.c.20.1 M00001558A:H05 89.F12.sp6:130738.Seq M00001561A:C05 39486 RTA00000128A.m.22.2 M00001561A:C05 39486 79.B8.sp6:130035.Seq M00001564A:B12 5053 RTA00000184AF.o.12.1 M00001578B:E04 23001 RTA00000185AF.c.24.1 M00001579D:C03 6539 90.G1.sp6:130931.Seq M00001579D:C03 6539 173.A12.SP6:134080.Seq M00001579D:C03 6539 RTA00000185AF.d.11.1 M00001582D:F05 RTA00000185AF.d.24.1 M00001587A:B11 39380 RTA00000129A.e.24.1 M00001587A:B11 39380 79.E8.sp6:130071.Seq M00001604A:F05 39391 RTA00000138A.c.3.1 M00001604A:F05 39391 79.A9.sp6:130024.Seq M00001624A:B06 3277 RTA00000138A.l.5.1 M00001624A:B06 3277 217.E1.sp6:139406.Seq M00001624A:B06 3277 90.B4.sp6:130874.Seq M00001630B:H09 5214 90.D4.sp6:130898.Seq M00001630B:H09 5214 122.C2.sp6:132098.Seq M00001630B:H09 5214 RTA00000186AF.g.11.1 M00001651A:H01 RTA00000186AF.n.7.1 M00001651A:H01 90.A5.sp6:130863.Seq M00001677C:E10 14627 RTA00000187AF.g.23.1 M00001679C:F01 78091 90.C7.sp6:130889.Seq M00001679C:F01 78091 RTA00000187AF.j.6.1 M00001679C:F01 78091 176.G5.sp6:134588.Seq M00001686A:E06 4622 RTA00000187AF.m.15.2 M00003796C:D05 5619 RTA00000188AF.1.9.1.Seq_THC167845 M00003796C:D05 5619 RTA00000188AF.1.9.1 M00003826B:A06 11350 RTA00000189AF.a.24.2 M00003826B:A06 11350 90.F9.sp6:130927.Seq M00003833A:E05 21877 RTA00000189AF.b.21.1 M00003837D:A01 7899 90.H9.sp6:130951.Seq M00003837D:A01 7899 RTA00000189AF.c.10.1 M00003846B:D06 6874 RTA00000189AF.e.9.1 M00003846B:D06 6874 90.C10.sp6:130892.Seq M00003879B:D10 31587 RTA00000189AF.1.20.1 M00003879B:D10 31587 90.C12.sp6:130894.Seq M00003879D:A02 14507 90.D12.sp6:130906.Seq M00003879D:A02 14507 RTA00000189AR.1.23.2 M00003891C:H09 90.G12.sp6:130942.Seq M00003891C:H09 RTA00000189AF.p.8.1 M00003912B:D01 12532 99.D1.sp6:131266.Seq M00003912B:D01 12532 RTA00000190AF.g.2.1 M00004072B:B05 17036 RTA00000191AF.j.10.1 M00004081C:D12 14391 RTA00000191AF.1.7.1 M00004111D:A08 6874 RTA00000192AF.a.14.1 M00004111D:A08 6874 99.F5.sp6:131294.Seq M00004121B:G01 177.H4.sp6:134791.Seq M00004121B:G01 99.H5.sp6:131318.Seq M00004121B:G01 RTA00000192AF.c.2.1 M00004138B:H02 13272 99.A6.sp6:131235.Seq M00004138B:H02 13272 RTA00000192AF.e.3.1 M00004151D:B08 16977 RTA00000192AF.g.3.1 M00004169C:C12 5319 99.E6.sp6:131283.Seq M00004169C:C12 5319 RTA00000192AF.i.12.1 M00004169C:C12 5319 123.F7.sp6:132331.Seq M00004183C:D07 16392 RTA00000192AF.l.1.1 M00004183C:D07 16392 RTA00000192AF.l.1.1.Seq_THC202071 M00004230B:C07 7212 RTA00000193AF.b.14.1 M00004230B:C07 7212 99.D8.sp6:131273.Seq M00004249D:F10 RTA00000193AF.c.21.1.Seq_THC222602 M00004249D:F10 RTA00000193AF.c.21.1 M00004275C:C11 16914 99.A9.sp6:131238.Seq M00004275C:C11 16914 RTA00000193AF.f.5.1 M00004283B:A04 14286 RTA00000193AF.f.22.1 M00004285B:E08 56020 RTA00000193AF.g.2.1 M00004327B:H04 RTA00000193AF.j.20.1 M00004377C:F05 2102 RTA00000193AF.n.7.1 M00004384C:D02 RTA00000193AF.n.15.1 M00004384C:D02 RTA00000193AF.n.15.1.Seq_THC215687 M00004461A:B08 RTA00000194AR.a.10.2 M00004461A:B09 RTA00000194AF.a.11.1 M00004691D:A05 RTA00000194AF.c.23.1 M00004896A:C07 RTA00000194AF.d.13.1

The above material has been deposited with the American Type Culture Collection, Rockville, Md., under the accession number indicated. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for purposes of Patent Procedure. The deposit will be maintained for a period of 30 years following issuance of this patent, or for the enforceable life of the patent, whichever is greater. Upon issuance of the patent, the deposit will be available to the public from the ATCC without restriction.

This deposit is provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones

Where the ATCC deposit is composed of a pool of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

Example 14 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

Human colon cancer cell line Km12L4-A (Morika, W. A. K. et al., Cancer Research (1988) 48:6863) was used to construct a cDNA library from mRNA isolated from the cells. As described in the above overview, a total of 4,693 sequences expressed by the Km12L4-A cell line were isolated and analyzed; most sequences were about 275-300 nucleotides in length. The KM12L4-A cell line is derived from the KM12C cell line. The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Ann. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246).

The sequences were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of 43 sequences. The remaining sequences were then used in a BLASTN vs. Genbank search with search parameters of greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰, which search resulted in the discarding of 1,432 sequences. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the Genbank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). This search resulted in discard of 98 sequences as having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search resulted in discard of 1771 sequences (sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰; sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded). Second, a BLASTN vs. Patent GeneSeq database resulted in discard of 15 sequences (greater than 99% identity; p value less than 1×10⁻⁴⁰; greater than 99% overlap).

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 2502 sequences listed in the accompanying Sequence Listing. The Sequence Listing is arranged beginning with sequences with no similarity to any sequence in a database searched, and ending with sequences with the greatest similarity. Each identified polynucleotide represents sequence from at least a partial mRNA transcript. Polynucleotides that were determined to be novel were assigned a sequence identification number.

The novel polynucleotides were assigned sequence identification numbers SEQ ID NOS:845-3346. The DNA sequences corresponding to the novel polynucleotides are provided in the Sequence Listing. The majority of the sequences are presented in the Sequence Listing in the 5′ to 3′ direction. A small number of sequences are listed in the Sequence Listing in the 5′ to 3′ direction but the sequence as written is actually 3′ to 5′. These sequences are readily identified with the designation “AR” in the Sequence Name in Table 17 (inserted before the claims). The sequences correctly listed in the 5′ to 3′ direction in the Sequence Listing are designated “AF.” Table 17 provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the filing date of the U.S. priority application in which the sequence was first filed; 3) the SEQ ID NO assigned to the sequence in the priority application; 4) the sequence name used as an internal identifier of the sequence; 5) the name assigned to the clone from which the sequence was isolated; and 6) the number of the cluster to which the sequence is assigned (Cluster ID; where the cluster ID is 0, the sequence was not assigned to any cluster

Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene. In addition, some sequences are identified with multiple SEQ ID NOS, since these sequences were present in more than one filing. For example, SEQ ID NO:931 and SEQ ID NO:1844 represent the same sequence.

In order to confirm the sequences of SEQ ID NOS:845-3346, inserts of the clones corresponding to these polynucleotides were re-sequenced. These “validation” sequences are provided in SEQ ID NOS:3347-5106. Of these validation sequences, SEQ ID NOS:3384, 4389, 4407, 5355, 5570, and 5593 are not true validation sequences. Instead, SEQ ID NOS: 4389, 5355, 5570, and 5593 represent “placeholder” sequences, i.e., sequences that were inserted into the Sequence Listing only to prevent renumbering of the subsequent sequences during generation of the Sequence Listing. Thus, reference to “SEQ ID NOS:845-6096,” “SEQ ID NOS:845-5950,” or other ranges of SEQ ID NOS that include these placeholder sequences should be read to exclude SEQ ID NOS: 4389, 5355, 5570, and 5593.

The validation sequences were often longer than the original polynucleotide sequences they validate, and thus often provide additional sequence information. Validation sequences can be correlated with the original sequences they validate by referring to Table 17. For example, validation sequences of many SEQ ID NOS share the clone name of the sequence that they validate.

Example 15 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS:845-3346, as well as the validation sequences were translated in all three reading frames to determine the best alignment with the individual sequences. These amino acid sequences and nucleotide sequences are referred, generally, as query sequences, which are aligned with the individual sequences. Query and individual sequences were aligned using the BLAST programs, available over the world wide web site of the NCBI. Again the sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above in Example 1.

Table 18 (inserted before the claims) shows the results of the alignments. Table 18 refers to each sequence by its SEQ ID NO:, the accession numbers and descriptions of nearest neighbors from the Genbank and Non-Redundant Protein searches, and the p values of the search results.

For each of “SEQ ID NOS:845-5950,” the best alignment to a protein or DNA sequence is included in Table 18. The activity of the polypeptide encoded by “SEQ ID NOS: 845-5950” is the same or similar to the nearest neighbor reported in Table 18. The accession number of the nearest neighbor is reported, providing a reference to the activities exhibited by the nearest neighbor. The search program and database used for the alignment also are indicated as well as a calculation of the p value.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of “SEQ ID NOS: 845-5950.” The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of “SEQ ID NOS: 845-5950.”

“SEQ ID NOS: 845-5950” and the translations thereof may be human homologs of known genes of other species or novel allelic variants of known human genes. In such cases, these new human sequences are suitable as diagnostics or therapeutics. As diagnostics, the human sequences “SEQ ID NOS: 845-5950” exhibit greater specificity in detecting and differentiating human cell lines and types than homologs of other species. The human polypeptides encoded by “SEQ ID NOS:845-5950” are likely to be less immunogenic when administered to humans than homologs from other species. Further, on administration to humans, the polypeptides encoded by “SEQ ID NOS: 845-5950” can show greater specificity or can be better regulated by other human proteins than are homologs from other species.

Example 16 Members of Protein Families

The validation sequences (“SEQ ID NOS:3347-5950”) were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 19, inserted prior to claims). Thus the invention encompasses fragments, fusions, and variants of such polynucleotides that retain biological activity associated with the protein family and/or functional domain identified herein.

Start and stop indicate the position within the individual sequences that align with the query sequence having the indicated SEQ ID NO. The direction (Dir) indicates the orientation of the query sequence with respect to the individual sequence, where forward (for) indicates that the alignment is in the same direction (left to right) as the sequence provided in the Sequence Listing and reverse (rev) indicates that the alignment is with a sequence complementary to the sequence provided in the Sequence Listing.

Some polynucleotides exhibited multiple profile hits because, for example, the particular sequence contains overlapping profile regions, and/or the sequence contains two different functional domains. These profile hits are described in more detail below. The acronyms used in Table 19 are provided in parentheses following the full name of the protein family or functional domain to which they refer.

TABLE 19 Polynucleotides encoding gene products of a protein family or having a known functional domain(s). SEQ ID Biological NO: Validation Sequence Activity (Profile) Start Stop Score Direction 4764 393.E10.sp6:148957 7tm_1 531 710 9520 for 3511 172.F10.sp6:133946 7tm_2 45 724 8708 rev 3602 177.C6.sp6:134733 7tm_2 41 697 9828 rev 3777 184.C7.sp6:135556 7tm_2 3 834 8987 for 3973 121.E12.sp6:131940 7tm_2 245 1324 9550 rev 4209 172.A7.sp6:133883 7tm_2 94 761 8743 rev 4262 123.F9.sp6:132333 7tm_2 203 585 8785 rev 4263 123.F9.sp6:132333 7tm_2 203 585 8785 rev 4441 394.G2.sp6:149165 7tm_2 73 793 9209 for 4492 370.C5.sp6:141726 7tm_2 76 770 9269 for 4530 370.B1.sp6:141710 7tm_2 89 662 8791 for 4539 368.A12.sp6:141322 7tm_2 121 719 9015 rev 4540 368.A12.sp6:141322 7tm_2 121 719 9015 rev 5016 219.C10.sp6:139007 7tm_2 46 774 11394 rev 5060 368.D11.sp6:141357 7tm_2 66 775 9384 rev 5072 368.A11.sp6:141321 7tm_2 7 1079 9097 for 5285 99.F7.sp6:131296 7tm_2 534 1265 10956 rev 5286 99.F7.sp6:131296 7tm_2 534 1265 10956 rev 5326 100.D2.sp6:131459 7tm_2 122 1404 9296 rev 5339 395.B12.sp6:149307 7tm_2 79 1432 10427 rev 5369 90.B4.sp6:130874 7tm_2 4 691 9435 for 5460 100.D5.sp6:131462 7tm_2 655 1349 9255 for 5497 100.D7.sp6:131464 7tm_2 357 1346 11461 rev 5498 100.D7.sp6:131464 7tm_2 357 1346 11461 rev 5502 100.H6.sp6:131511 7tm_2 119 1035 10001 rev 5503 100.G6.sp6:131499 7tm_2 363 1188 9901 rev 5504 100.F6.sp6:131487 7tm_2 50 1127 8799 for 5505 100.F6.sp6:131487 7tm_2 50 1127 8799 for 5554 367.H9.sp6:141210 7tm_2 143 1266 11883 rev 5599 370.F4.sp6:141761 7tm_2 78 704 8942 for 5700 367.H11.sp6:141212 7tm_2 176 1227 9975 rev 5729 123.E10.sp6:132322 7tm_2 210 691 9071 rev 5744 123.E10.sp6:132322 7tm_2 210 691 9071 rev 5745 123.E10.sp6:132322 7tm_2 210 691 9071 rev 3500 176.H11.sp6:134606 ANK 207 290 4450 for 3399 180.C9.sp6:135947 asp 156 670 6710 for 4476 368.H11.sp6:141405 asp 136 1226 6880 rev 5049 368.B5.sp6:141327 asp 309 806 6073 for 5095 369.D6.sp6:141546 asp 434 1332 6263 rev 5097 396.F9.sp6:149544 asp 97 1106 5999 rev 5105 216.G10.sp6:139247 asp 74 703 6188 rev 5209 122.H12.sp6:132168 asp 152 1040 6183 rev 5342 80.H6.sp6:130297 asp 61 418 5944 rev 5508 172.E5.sp6:133929 asp 219 976 6434 for 5562 185.D9.sp6:135762 asp 31 872 5944 rev 5577 185.D9.sp6:135762 asp 31 872 5944 rev 5590 176.B10.sp6:134533 asp 253 1446 6079 rev 5666 177.F3.sp6:134766 asp 0 894 6336 rev 5698 184.F11.sp6:135596 asp 61 737 6416 rev 5700 367.H11.sp6:141212 asp 81 1187 6182 rev 5773 180.E6.sp6:135968 asp 81 706 6150 for 5775 180.E6.sp6:135968 asp 81 706 6150 for 3567 180.F2.sp6:135976 ATPases 135 627 11664 for 3686 217.H11.sp6:139452 ATPases 2 701 5972 for 3863 216.B1.sp6:139178 ATPases 170 616 6150 for 3890 121.B8.sp6:131900 ATPases 13 635 5867 rev 4034 80.D2.sp6:130245 ATPases 13 386 6068 for 4134 176.C6.sp6:134541 ATPases 85 579 5883 for 4514 369.C10.sp6:141538 ATPases 329 730 6206 for 4842 394.H8.sp6:149183 ATPases 21 571 5954 rev 4963 218.F11.sp6:138852 ATPases 313 816 6057 for 5003 219.A7.sp6:138980 ATPases 88 662 6145 for 5067 368.F9.sp6:141379 ATPases 178 648 5937 for 5228 181.G11.sp6:135354 ATPases 362 769 5900 rev 5317 369.B4.sp6:141520 ATPases 4 412 14130 for 5384 218.C8.sp6:138813 ATPases 12 576 5782 rev 5404 404.G6.sp6:162933 ATPases 86 605 6001 rev 5533 367.H8.sp6:141209 ATPases 17 476 5905 rev 5629 184.E5.sp6:135578 ATPases 184 632 5943 for 5636 184.C6.sp6:135555 ATPases 333 813 5773 for 5691 184.B11.sp6:135548 ATPases 14 498 6140 for 5885 377.C1.sp6:141918 ATPases 4 655 5933 for 4248 176.F10.sp6:134581 Bcl-2 69 356 16419 for 4880 367.F5.sp6:141182 bromodomain 40 210 8810 for 5333 369.D3.sp6:141543 bromodomain 63 230 10270 for 4252 172.E1.sp6:133925 BZIP 146 298 4066 for 4795 393.G5.sp6:148976 BZIP 116 304 5931 for 5694 172.E9.sp6:133933 BZIP 91 260 4366 for 4462 370.B12.sp6:141721 cyclin 118 324 8980 for 4739 395.G6.sp6:149361 cyclin 11 281 6930 for 5380 395.G8.sp6:149363 cyclin 12 279 5950 for 5299 99.F5.sp6:131294 Cys-protease 72 348 18479 for 5528 180.D1.sp6:135951 Cys-protease 38 992 10103 rev 5532 180.D1.sp6:135951 Cys-protease 38 992 10103 rev 5645 177.E4.sp6:134755 Cys-protease 48 326 19999 for 5503 100.G6.sp6:131499 DAG_PE_bind 605 702 6290 rev 5665 377.C8.sp6:141925 Dead_box_helic 172 828 7867 rev 5927 216.A1.sp6:139166 Dead_box_helic 44 589 26532 for 3578 177.G4.sp6:134779 EFhand 79 153 3780 for 3737 185.A1.sp6:135718 EFhand 287 358 2580 rev 4619 377.A5.sp6:141898 EFhand 477 563 3010 for 4900 367.B7.sp6:141136 EFhand 225 272 2500 rev 4996 218.B10.sp6:138803 EFhand 40 114 2640 rev 4997 218.B10.sp6:138803 EFhand 40 114 2640 rev 4998 218.C10.sp6:138815 EFhand 39 113 2640 rev 5749 393.H12.sp6:148995 EFhand 145 231 4640 for 5787 219.A9.sp6:138982 EFhand 685 750 2550 rev 3693 218.B5.sp6:138798 Ets_Nterm 340 531 10400 for 3572 180.A2.sp6:135916 FNtypeII 291 423 6400 rev 3862 216.C1.sp6:139190 FNtypeII 501 634 6460 for 5340 218.G1.sp6:138854 FNtypeII 20 141 6180 rev 5758 393.H8.sp6:148991 FNtypeII 448 576 6110 for 3348 181.C3.sp6:135298 G-alpha 66 715 8084 rev 4134 176.C6.sp6:134541 G-alpha 62 690 9062 for 5132 121.B4.sp6:131896 G-alpha 46 447 21415 for 5288 217.D12.sp6:139405 G-alpha 15 702 40404 for 5406 404.B7.sp6:162874 G-alpha 120 682 8424 for 3347 180.A11.sp6:135925 helicase_C 165 479 4494 for 5313 369.C4.sp6:141532 helicase_C 559 756 3732 rev 5864 185.D12.sp6:135765 helicase_C 381 534 5000 for 5085 396.H8.sp6:149567 homeobox 80 230 5170 for 3394 180.E5.sp6:135967 mkk 342 612 5791 for 4251 172.F1.sp6:133937 mkk 94 669 5688 rev 4295 123.A2.sp6:132266 mkk 26 378 7889 for 4444 394.B3.sp6:149106 mkk 32 782 9544 for 4490 370.H4.sp6:141785 mkk 18 307 9394 for 4524 369.G11.sp6:141587 mkk 182 725 5375 for 5019 219.H10.sp6:139067 mkk 280 723 15454 for 5049 368.B5.sp6:141327 mkk 249 725 5502 for 5122 181.C9.sp6:135304 mkk 168 880 5551 rev 5166 121.F6.sp6:131946 mkk 111 730 5399 for 5621 177.E2.sp6:134753 mkk 288 636 5720 rev 5326 100.D2.sp6:131459 PDEase 849 1195 5945 for 3422 181.H11.sp6:135366 protkinase 116 710 5531 for 3556 177.G7.sp6:134782 protkinase 6 511 5445 for 3679 218.C1.sp6:138806 protkinase 127 747 5492 for 3687 218.E1.sp6:138830 protkinase 64 726 5592 rev 3815 217.F4.sp6:139421 protkinase 83 702 5818 rev 3853 217.A4.sp6:139361 protkinase 57 682 5395 rev 3928 121.E2.sp6:131930 protkinase 69 658 5593 rev 4070 100.D8.sp6:131465 protkinase 174 620 5453 for 4118 100.C3.sp6:131448 protkinase 228 736 5616 for 4200 172.B5.sp6:133893 protkinase 148 715 5381 for 4221 172.B6.sp6:133894 protkinase 119 775 5616 for 4295 123.A2.sp6:132266 protkinase 24 384 9797 for 4444 394.B3.sp6:149106 protkinase 357 780 11395 for 4479 377.G11.sp6:141976 protkinase 117 739 5992 for 4490 370.H4.sp6:141785 protkinase 24 275 8338 for 4509 370.F2.sp6:141759 protkinase 33 800 5658 for 4513 369.B10.sp6:141526 protkinase 1 482 5504 rev 4544 369.D2.sp6:141542 protkinase 28 661 5428 for 4554 369.G6.sp6:141582 protkinase 71 631 5751 for 4635 396.C11.sp6:149510 protkinase 27 709 5793 rev 4749 393.H7.sp6:148990 protkinase 88 680 5470 rev 4763 393.D10.sp6:148945 protkinase 72 594 5617 for 4888 367.G4.sp6:141193 protkinase 30 699 5439 for 4916 368.B2.sp6:141324 protkinase 44 800 5556 for 4961 218.D11.sp6:138828 protkinase 38 781 6423 for 5019 219.H10.sp6:139067 protkinase 277 717 15720 for 5217 216.E5.sp6:139218 protkinase 115 710 5537 for 5413 100.C10.sp6:131455 protkinase 56 783 5556 rev 5599 370.F4.sp6:141761 protkinase 39 803 5635 for 5604 370.F3.sp6:141760 protkinase 188 775 5771 for 5651 184.H3.sp6:135612 protkinase 23 699 5515 for 5903 180.B5.sp6:135931 protkinase 182 671 5718 rev 5946 393.F4.sp6:148963 protkinase 28 650 5345 for 4515 369.D10.sp6:141550 ras 12 332 9802 for 4780 393.A3.sp6:148902 Thioredox 0 263 5887 rev 4771 393.F11.sp6:148970 TNFR_c6 151 261 6445 for 3800 184.E10.sp6:135583 transmembrane4 19 483 8339 rev 3825 217.E6.sp6:139411 transmembrane4 83 728 8417 for 4680 396.C9.sp6:149508 transmembrane4 300 924 9444 rev 4882 367.A6.sp6:141123 transmembrane4 32 495 8407 rev 5208 123.A1.sp6:132265 transmembrane4 1289 1548 8114 rev 5250 122.C1.sp6:132097 transmembrane4 6 535 8122 for 5275 122.E4.sp6:132124 transmembrane4 10 530 8829 for 5285 99.F7.sp6:131296 transmembrane4 613 1253 9443 rev 5286 99.F7.sp6:131296 transmembrane4 613 1253 9443 rev 5497 100.D7.sp6:131464 transmembrane4 335 1207 8255 rev 5498 100.D7.sp6:131464 transmembrane4 335 1207 8255 rev 5554 367.H9.sp6:141210 transmembrane4 398 1130 8352 rev 5788 180.H7.sp6:136005 transmembrane4 356 983 8356 rev 4225 176.D9.sp6:134556 trypsin 164 764 9670 rev 5528 180.D1.sp6:135951 trypsin 371 1229 10479 rev 5532 180.D1.sp6:135951 trypsin 371 1229 10479 rev 3598 177.H6.sp6:134793 WD_domain 345 437 6510 for 3890 121.B8.sp6:131900 WD_domain 98 193 6400 for 4071 100.B10.sp6:131443 WD_domain 544 642 6590 for 5087 121.A8.sp6:131888 WD_domain 93 188 6400 for 5890 185.F10.sp6:135787 WD_domain 382 480 5880 for 3973 121.E12.sp6:131940 Wnt_dev_sign 101 821 12160 rev 4017 99.G6.sp6:131307 Wnt_dev_sign 49 880 12334 rev 4234 176.C9.sp6:134544 Wnt_dev_sign 249 854 11038 rev 4235 176.C9.sp6:134544 Wnt_dev_sign 249 854 11038 rev 4500 370.G6.sp6:141775 Wnt_dev_sign 211 785 11490 rev 4680 396.C9.sp6:149508 Wnt_dev_sign 282 1017 12318 rev 5097 396.F9.sp6:149544 Wnt_dev_sign 482 1298 11217 rev 5174 122.A2.sp6:132074 Wnt_dev_sign 94 933 12383 rev 5203 123.B2.sp6:132278 Wnt_dev_sign 538 1435 11785 for 5208 123.A1.sp6:132265 Wnt_dev_sign 760 1544 12660 rev 5219 122.G10.sp6:132154 Wnt_dev_sign 29 884 11603 rev 5229 122.A2.sp6:132074 Wnt_dev_sign 94 933 12383 rev 5253 121.F12.sp6:131952 Wnt_dev_sign 9 734 11167 rev 5285 99.F7.sp6:131296 Wnt_dev_sign 560 1399 13749 rev 5286 99.F7.sp6:131296 Wnt_dev_sign 560 1399 13749 rev 5379 395.F10.sp6:149353 Wnt_dev_sign 100 907 11535 rev 5430 123.A4.sp6:132268 Wnt_dev_sign 80 1122 11249 rev 5449 404.D5.sp6:162896 Wnt_dev_sign 31 816 11304 rev 5497 100.D7.sp6:131464 Wnt_dev_sign 467 1314 11882 rev 5498 100.D7.sp6:131464 Wnt_dev_sign 467 1314 11882 rev 5509 177.B11.sp6:134726 Wnt_dev_sign 137 1266 12708 rev 5512 177.B11.sp6:134726 Wnt_dev_sign 137 1266 12708 rev 5526 177.B11.sp6:134726 Wnt_dev_sign 137 1266 12708 rev 5554 367.H9.sp6:141210 Wnt_dev_sign 692 1481 12886 rev 5562 185.D9.sp6:135762 Wnt_dev_sign 129 890 11145 rev 5568 377.D2.sp6:141931 Wnt_dev_sign 400 1227 11044 rev 5577 185.D9.sp6:135762 Wnt_dev_sign 129 890 11145 rev 5700 367.H11.sp6:141212 Wnt_dev_sign 295 1669 13366 rev 5710 377.D4.sp6:141933 Wnt_dev_sign 549 1380 14522 rev 5769 219.B12.sp6:138997 Wnt_dev_sign 312 1214 13188 rev 5803 219.B12.sp6:138997 Wnt_dev_sign 312 1214 13188 rev 4253 172.D1.sp6:133913 Y_phosphatase 476 804 6932 for 4262 123.F9.sp6:132333 Y_phosphatase 28 439 6096 rev 4263 123.F9.sp6:132333 Y_phosphatase 28 439 6096 rev 4501 370.H6.sp6:141787 Y_phosphatase 148 554 6481 for 4648 404.B10.sp6:162877 Y_phosphatase 104 466 6446 rev 4650 404.D10.sp6:162901 Y_phosphatase 9 614 6516 for 4818 395.F2.sp6:149345 Y_phosphatase 164 645 6093 rev 5082 121.E9.sp6:131937 Y_phosphatase 240 777 6147 rev 5107 216.F10.sp6:139235 Y_phosphatase 21 504 6342 for 5187 122.E9.sp6:132129 Y_phosphatase 381 807 6036 rev 5207 123.B1.sp6:132277 Y_phosphatase 61 510 6229 rev 5278 219.F4.sp6:139037 Y_phosphatase 2 261 10353 for 5317 369.B4.sp6:141520 Y_phosphatase 231 768 6110 rev 5473 404.E11.sp6:162914 Y_phosphatase 580 920 6005 rev 5938 217.A3.sp6:139360 Y_phosphatase 263 622 6222 rev 3582 177.A6.sp6:134709 Zincfing_C2H2 65 127 4380 for 3604 177.A6.sp6:134709 Zincfing_C2H2 65 127 4380 for 3676 218.B2.sp6:138795 Zincfing_C2H2 94 156 4940 for 4580 377.H8.sp6:141985 Zincfing_C2H2 495 557 4850 for 4606 377.G2.sp6:141967 Zincfing_C2H2 52 114 4380 for 4607 377.G2.sp6:141967 Zincfing_C2H2 52 114 4380 for 5638 377.G4.sp6:141969 Zincfing_C2H2 247 308 3930 for 5934 185.C4.sp6:135745 Zincfing_C2H2 238 300 4540 for 4618 377.E4.sp6:141945 Zincfing_C3HC4 128 244 9335 for 5321 181.E3.sp6:135322 Zincfing_C3HC4 321 445 8221 for

a) Seven Transmembrane Integral Membrane Proteins—Rhodopsin Family (7tm_(—)1). Several of the validation sequences, and thus their corresponding sequence within SEQ ID NOS:845-3346, correspond to a sequence encoding a polypeptide that is a member of the seven transmembrane receptor rhodopsin family. G-protein coupled receptors of the seven transmembrane rhodopsin family (also called R7G) are an extensive group of hormones, neurotransmitters, and light receptors which transduce extracellular signals by interaction with guanine nucleotide-binding (G) proteins (Strosberg A. D. Eur. J. Biochem. (1991) 196:1, Kerlavage A. R. Curr. Opin. Struct. Biol. (1991) 1:394, Probst, et al., DNA Cell Biol. (1992) 11:1, Savarese, et al., Biochem. J. (1992) 283:1. The receptors that are currently known to belong to this family are: 1) 5-hydroxytryptamine (serotonin) 1A to 1F, 2A to 2C, 4, 5A, 5B, 6 and 7 (Branchek T., Curr. Biol. (1993) 3:315); 2) acetylcholine, muscarinic-type, M1 to M5; 3) adenosine A1, A2A, A2B and A3 (Stiles G. L. J. Biol. Chem. (1992) 267:6451; 4) adrenergic alpha-1A to -1C; alpha-2A to -2D; beta-1 to -3 (Friell T. et al., Trends Neurosci. (1988) 11:321); 5) angiotensin II types I and II; 6) bombesin subtypes 3 and 4; 7) bradykinin B1 and B2; 8) c3a and C5a anaphylatoxin; 9) cannabinoid CB1 and CB2; 10) chemokines C-C CC-CKR-1 to CC-CKR-8; 11) Chemokines C-X-C CXC-CKR-1 to CXC-CKR-4; 12) Cholecystokinin-A and cholecystokinin-B/gastrin Dopamine D1 to D5 (Stevens C. F., Curr. Biol. (1991) 1:20); 13) Endothelin ET-a and ET-b (Sakurai T. et al., Trends Pharmacol. Sci. (1992) 13:103-107); 14) fMet-Leu-Phe (fMLP) (Nformyl peptide); 15) Follicle stimulating hormone (FSH-R); 16) Galanin; 17) Gastrin-releasing peptide (GRP-R); 18) Gonadotropin-releasing hormone (GNRH-R); 19) Histamine H1 and H2 (gastric receptor I); 20) Lutropin-choriogonadotropic hormone (LSH-R) (Salesse R., et al., Biochimie (1991) 73:109); 21) Melanocortin MC1R to MC5R; 22) Melatonin; 23) Neuromedin B (NMB-R); 24) Neuromedin K (NK-3R); 25) Neuropeptide Y types 1 to 6; 26) Neurotensin (NT-R); 27) Octopamine (tyramine), from insects; 28) Odorants (Lancet D., et al., Curr. Biol. (1993)3:668; 29) Opioids delta-, kappa- and mu-types (Uhl G. R., et al., Trends Neurosci. (1994) 17:89; 30) Oxytocin (OT-R); 31) Platelet activating factor (PAF-R); 32) Prostacyclin; 33) Prostaglandin D2; 34) Prostaglandin E2, EP1 to EP4 subtypes; 35) Prostaglandin F2; 36) Purinoreceptors (ATP) (Barnard E. A., et al., Trends Pharmacol. Sci. (1994)15:67; 37); Somatostatin types 1 to 5; 38) Substance-K (NK-2R); Substance-P (NK-1R); 39) Thrombin; 40) Thromboxane A2; 41) Thyrotropin (TSH-R) (Salesse R., et al., Biochimie (1991) 73:109); 42) Thyrotropin releasing factor (TRH-R); 42) Vasopressin V1a, V1b and V2; 43) Visual pigments (opsins and rhodopsin) (Applebury M. L., et al., Vision Res. (1986) 26:1881; 44) Proto-oncogene mas; 45) A number of orphan receptors (whose ligand is not known) from mammals and birds; 46) Caenorhabditis elegans putative receptors C06G4.5, C38C10.1, C43C3.2; 47) T27D1.3 and ZC84.4; 48) Three putative receptors encoded in the genome of cytomegalovirus: US27, US28, and UL33; and 49) ECRF3, a putative receptor encoded in the genome of herpesvirus saimiri.

The structure of these receptors is thought to be identical. They have seven hydrophobic regions, each of which most probably spans the membrane. The N-terminus is located on the extracellular side of the membrane and is often glycosylated, while the C-terminus is cytoplasmic and generally phosphorylated. Three extracellular loops alternate with three intracellular loops to link the seven transmembrane regions. Most, but not all of these receptors, lack a signal peptide. The most conserved parts of these proteins are the transmembrane regions and the first two cytoplasmic loops. A conserved acidic-Arg-aromatic triplet is present in the N-terminal extremity of the second cytoplasmic loop (Attwood T. K., Eliopoulos E. E., Findlay J. B. C. Gene (1991) 98:153-159) and could be implicated in the interaction with G proteins.

b) Seven Transmembrane Integral Membrane Proteins—Secretin Family (7tm_(—)2). Several of the validation sequences, and thus their corresponding sequence in the sequence listing, correspond to a sequence encoding a polypeptide that is a member of the seven transmembrane receptor secretin family. A number of peptide hormones bind to G-protein coupled receptors that, while structurally similar to the majority of G-protein coupled receptors (R7G) (see profile for 7 transmembrane receptors (rhodopsin family), do not show any similarity at the level of their sequence, thus new family whose current known members (Jueppner et al. Science (1991) 254:1024; Hamann et al. Genomnics (1996) 32:144) are: 1) calcitonin receptor, 2) calcitonin gene-related peptide receptor; 3) corticotropin releasing factor receptor types 1 and 2; 4) gastric inhibitory polypeptide receptor; 5) glucagon receptor; 6) glucagon-like peptide 1 receptor; 7) growth hormone-releasing hormone receptor; 7) parathyroid hormone/parathyroid hormone-related peptide types 1 and 2; 8) pituitary adenylate cyclase activating polypeptide receptor; 9) secretin receptor; 10) vasoactive intestinal peptide receptor types 1 and 2; 10) insects diuretic hormone receptor; 11) Caenorhabditis elegans putative receptor C13B9.4; 12) Caenorhabditis elegans putative receptor ZK643.3; 13) human leucocyte CD97 (which contains 3 EGF-like domains in its N-terminal section); 14) human cell surface glycoprotein EMR1 (which contains 6 EGF-like domains in it N-terminal section); and 15) mouse cell surface glycoprotein F4/80 (which contains 7 EGF-like domains in its N-terminal section). All of 1) through 10) are coupled to G-proteins which activate both adenylyl cyclase and the phosphatidylinositol-calcium pathway.

Like classical R7G the secretin family of 7 transmembrane proteins contain seven transmembrane regions. Their N-terminus is located on the extracellular side of the membrane and potentially glycosylated, while their C-terminus is cytoplasmic. But apart from these topological similarities they do not share any region of sequence similarity and are therefore probably not evolutionary related.

Every receptor in the 7 transmember secretin family is encoded on multiple exons, and several of these functionally distinct products. The N-terminal extracellular domain of these receptors contains five conserved cysteines residues that may be involved in disulfide bonds, with a consensus pattern in the region that spans the first three cysteines. One of the most highly conserved regions spans the C-terminal part of the last transmembrane region and the beginning of the adjacent intracellular region. This second region is used as a second signature pattern.

c) Ank Repeats (ANK). The ankyrin motif is a 33 amino acid sequence named after the protein ankyrin which has 24 tandem 33-amino-acid motifs. Ank repeats were originally identified in the cell-cycle-control protein cdc10 (Breeden et al., Nature (1987) 329:651). Proteins containing ankyrin repeats include ankyrin, myotropin, I-kappaB proteins, cell cycle protein cdc10, the Notch receptor (Matsuno et al., Development (1997) 124(21):4265); G9a (or BAT8) of the class III region of the major histocompatibility complex (Biochem J. 290:811-818, 1993), FABP, GABP, 53BP2, Lin12, glp-1, SW14, and SW16. The functions of the ankyrin repeats are compatible with a role in protein-protein interactions (Bork, Proteins (1993) 17(4):363; Lambert and Bennet, Eur. J. Biochem. (1993) 211:1; Kerr et al., Current Op. Cell Biol. (1992) 4:496; Bennet et al., J. Biol. Chem. (1980) 255:6424).

The 90 kD N-terminal domain of ankyrin contains a series of 24 33-amino-acid ank repeats. (Lux et al., Nature (1990) 344:36-42, Lambert et al., PNAS USA (1990) 87:1730.) The 24 ank repeats form four folded subdomains of 6 repeats each. These four repeat subdomains mediate interactions with at least 7 different families of membrane proteins. Ankyrin contains two separate binding sites for anion exchanger dimers. One site utilizes repeat subdomain two (repeats 7-12) and the other requires both repeat subdomains 3 and 4 (repeats 13-24). Since the anion exchangers exist in dimers, ankyrin binds 4 anion exchangers at the same time (Michaely and Bennett, J. Biol. Chem. (1995) 270(37):22050). The repeat motifs are involved in ankyrin interaction with tubulin, spectrin, and other membrane proteins. (Lux et al., Nature (1990) 344:36.)

The Rel/NF-kappaB/Dorsal family of transcription factors have activity that is controlled by sequestration in the cytoplasm in association with inhibitory proteins referred to as I-kappaB. (Gilmore, Cell (1990) 62:841; Nolan and Baltimore, Curr Opin Genet Dev. (1992) 2:211; Baeuerle, Biochim Biophys Acta (1991) 1072:63; Schmitz et al., Trends Cell Biol. (1991) 1:130.) I-kappaB proteins contain 5 to 8 copies of 33 amino acid ankyrin repeats and certain NF-kappaB/rel proteins are also regulated by cis-acting ankyrin repeat containing domains including p105NF-kappaB which contains a series of ankyrin repeats (Diehl and Hannink, J. Virol. (1993) 67(12):7161). The I-kappaBs and Cactus (also containing ankyrin repeats) inhibit activators through differential interactions with the Rel-homology domain. The gene family includes proto-oncogenes, thus broadly implicating I-kappaB in the control of both normal gene expression and the aberrant gene expression that makes cells cancerous. (Nolan and Baltimore, Curr Opin Genet Dev. (1992) 2(2):211-220). In the case of rel/NF-kappaB and pp40/I-kappaB (both the ankyrin repeats and the carboxy-terminal domain are required for inhibiting DNA-binding activity and direct association of pp40/I-kappaB (with rel/NF-kappaB protein. The ankyrin repeats and the carboxy-terminal of pp40/I-kappaB (form a structure that associates with the rel homology domain to inhibit DNA binding activity (Inoue et al., PNAS USA (1992) 89:4333).

The 4 ankyrin repeats in the amino terminus of the transcription factor subunit GABP□ are required for its interaction with the GABP□ subunit to form a functional high affinity DNA-binding protein. These repeats can be crosslinked to DNA when GABP is bound to its target sequence. (Thompson et al., Science (1991) 253:762; LaMarco et al., Science (1991) 253:789). Myotrophin, a 12.5 kDa protein having a key role in the initiation of cardiac hypertrophy, comprises ankyrin repeats. The ankyrin repeats are characteristic of a hairpin-like protruding tip followed by a helix-turn-helix motif. The V-shaped helix-turn-helix of the repeats stack sequentially in bundles and are stabilized by compact hydrophobic cores, whereas the protruding tips are less ordered.

d) Eukaryotic Aspartyl Proteases (asp). Several of the validation sequences correspond to a sequence encoding a novel eukaryotic aspartyl protease. Aspartyl proteases, known as acid proteases, (EC 3.4.23.-) are a widely distributed family of proteolytic enzymes (Foltmann B., Essays Biochem. (1981) 17:52; Davies D. R., Annu. Rev. Biophys. Chem. (1990) 19:189; Rao J. K. M., et al., Biochemistry (1991) 30:4663) known to exist in vertebrates, fungi, plants, retroviruses and some plant viruses. Aspartate proteases of eukaryotes are monomeric enzymes which consist of two domains. Each domain contains an active site centered on a catalytic aspartyl residue. The two domains most probably evolved from the duplication of an ancestral gene encoding a primordial domain. Currently known eukaryotic aspartyl proteases include: 1) Vertebrate gastric pepsins A and C (also known as gastricsin); 2) Vertebrate chymosin (rennin), involved in digestion and used for making cheese; 3) Vertebrate lysosomal cathepsins D (EC 3.4.23.5) and E (EC 3.4.23.34); 4) Mammalian renin (EC 3.4.23.15) whose function is to generate angiotensin I from angiotensinogen in the plasma; 5) Fungal proteases such as aspergillopepsin A (EC 3.4.23.18), candidapepsin (EC 3.4.23.24), mucoropepsin (EC 3.4.23.23) (mucor rennin), endothiapepsin (EC 3.4.23.22), polyporopepsin (EC 3.4.23.29), and rhizopuspepsin (EC 3.4.23.21); and 6) Yeast saccharopepsin (EC 3.4.23.25) (proteinase A) (gene PEP4). PEP4 is implicated in posttranslational regulation of vacuolar hydrolases; 7) Yeast barrierpepsin (EC 3.4.23.35) (gene BAR1); a protease that cleaves alpha-factor and thus acts as an antagonist of the mating pheromone; and 8) Fission yeast sxa1 which is involved in degrading or processing the mating pheromones.

Most retroviruses and some plant viruses, such as badnaviruses, encode for an aspartyl protease which is an homodimer of a chain of about 95 to 125 amino acids. In most retroviruses, the protease is encoded as a segment of a polyprotein which is cleaved during the maturation process of the virus. It is generally part of the pol polyprotein and, more rarely, of the gag polyprotein. Because the sequence around the two aspartates of eukaryotic aspartyl proteases and around the single active site of the viral proteases is conserved, a single signature pattern can be used to identify members of both groups of proteases.

e) ATPases Associated with Various Cellular Activities (ATPases). Several of the validation sequences, correspond to a sequence that encodes a novel member of the “ATPases Associated with diverse cellular Activities” (AAA) protein family. The AAA protein family is composed of a large number of ATPases that share a conserved region of about 220 amino acids that contains an ATP-binding site (Froehlich et al., J. Cell Biol. (1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieri et al., BioEssays (1995) 17:639; see internet site at yeamob.pci.chemie.uni-tuebingen.de/A-AA/Description.html). The proteins that belong to this family either contain one or two AAA domains.

Proteins containing two AAA domains include: 1) Mammalian and drosophila NSF (N-ethylmaleimide-sensitive fusion protein) and the fungal homolog, SEC18, which are involved in intracellular transport between the endoplasmic reticulum and Golgi, as well as between different Golgi cisternae; 2) Mammalian transitional endoplasmic reticulum ATPase (previously known as p97 or VCP), which is involved in the transfer of membranes from the endoplasmic reticulum to the golgi apparatus. This ATPase forms a ring-shaped homooligomer composed of six subunits. The yeast homolog, CDC48, plays a role in spindle pole proliferation; 3) Yeast protein PAS1 essential for peroxisome assembly and the related protein PAS1 from Pichia pastoris; 4) Yeast protein AFG2; 5) Sulfolobus acidocaldarius protein SAV and Halobacterium salinarium cdcH, which may be part of a transduction pathway connecting light to cell division.

Proteins containing a single AAA domain include: 1) Escherichia coli and other bacteria ftsH (or hflB) protein. FtsH is an ATP-dependent zinc metallopeptidase that degrades the heat-shock sigma-32 factor, and is an integral membrane protein with a large cytoplasmic C-terminal domain that contain both the AAA and the protease domains; 2) Yeast protein YME1, a protein important for maintaining the integrity of the mitochondrial compartment. YME1 is also a zinc-dependent protease; 3) Yeast protein AFG3 (or YTA10). This protein also contains an AAA domain followed by a zinc-dependent protease domain; 4) Subunits from regulatory complex of the 26S proteasome (Hilt et al., Trends Biochem. Sci. (1996) 21:96), which is involved in the ATP-dependent degradation of ubiquitinated proteins, which subunits include: a) Mammalian 4 and homologs in other higher eukaryotes, in yeast (gene YTA5) and fission yeast (gene mts2); b) Mammalian 6 (TBP7) and homologs in other higher eukaryotes and in yeast (gene YTA2); c) Mammalian subunit 7 (MSS1) and homologs in other higher eukaryotes and in yeast (gene CIM5 or YTA3); d) Mammalian subunit 8 (P45) and homologs in other higher eukaryotes and in yeast (SUG1 or CIM3 or TBY1) and fission yeast (gene let1); e) Other probable subunits include human TBP1, which influences HIV gene expression by interacting with the virus tat transactivator protein, and yeast YTA1 and YTA6; 5) Yeast protein BCS1, a mitochondrial protein essential for the expression of the Rieske iron-sulfur protein; 6) Yeast protein MSP1, a protein involved in intramitochondrial sorting of proteins; 7) Yeast protein PAS8, and the corresponding proteins PAS5 from Pichia pastoris and PAY4 from Yarrowia lipolytica; 8) Mouse protein SKD1 and its fission yeast homolog (SpAC2G11.06); 9) Caenorhabditis elegans meiotic spindle formation protein mei-1; 10) Yeast protein SAP1′ 11) Yeast protein YTA7; and 12) Mycobacterium leprae hypothetical protein A2126A.

In general, the AAA domains in these proteins act as ATP-dependent protein clamps (Confalonieri et al. (1995) BioEssays 17:639). In addition to the ATP-binding ‘A’ and ‘B’ motifs, which are located in the N-terminal half of this domain, there is a highly conserved region located in the central part of the domain which was used in the development of the signature pattern.

f) Bcl-2 family (Bcl-2). SEQ ID NO:4248, and thus the corresponding sequence it validates, represents a polynucleotide encoding an apoptosis regulator protein of the Bcl-2, family. Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic) (Vaux, 1993, Curr. Biol. 3:877-878, and White, 1996, Genes Dev. 10:2859-2869). Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes, preventing their target cells from dying prematurely.

All proteins belonging to the Bcl-2 family (Reed et al., 1996, Adv. Exp. Med. Biol. 406:99-112) contain either a BH1, BH2, BH3, or BH4 domain. All anti-apoptotic proteins contain BH1 and BH2 domains; some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L), Bcl-w), which is never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 domain (except for Bad) necessary for dimerization with other proteins of Bcl-2 family and crucial for their killing activity; some of them also contain BH1 and BH2 domains (Bax, Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L). Proteins that are known to contain these domains are listed below.

1. Vertebrate protein Bcl-2. Bcl-2 blocks apoptosis; it prolongs the survival of hematopoietic cells in the absence of required growth factors and also in the presence of various stimuli inducing cellular death. Two isoforms of bcl-2 (alpha and beta) are generated by alternative splicing. Bcl-2 is expressed in a wide range of tissues at various times during development. It forms heterodimers with the Bax proteins. 2. Vertebrate protein Bcl-x. Two isoforms of Bcl-x (Bcl-x(L) and Bcl-x(S)) are generated by alternative splicing. While the longer product (Bcl-x(L)) can protect a growth-factor-dependent cell line from apoptosis, the shorter form blocks the protective effect of Bcl-2 and Bcl-x(L) and acts as an anti-anti-apoptosis protein. 3. Mammalian protein Bax. Bax blocks the anti-apoptosis ability of Bcl-2 with which it forms heterodimers. There is no evidence that Bax has any activity in the absence of Bcl-2. Three isoforms of bax (alpha, beta and gamma) are generated by alternative splicing. 4. Mammalian protein Bak, which promotes cell death and counteracts the protection from apoptosis provided by Bcl-2. 5. Mammalian protein Bcl-w, which promotes cell survival. 6. Mammalian protein bad, which promotes cell death, and counteracts the protection from apoptosis provided by Bcl-x(L), but not that of Bcl-2. 7. Human protein Bik, which promotes cell death, but cannot counteract the protection from apoptosis provided by Bcl-2. 8. Mouse protein Bid, which induces caspases and apoptosis, and counteracts the protection from apoptosis provided by Bcl-2. 9. Human induced myeloid leukemia cell differentiation protein MCL1. MCL1 is probably involved in programming of differentiation and concomitant maintenance of viability but not proliferation. Its expression increases early during phorbol ester induced differentiation in myeloid leukemia cell line ML-1. 10. Mouse hemopoietic-specific early response protein A1. 11. Mammalian activator of apoptosis Harakiri (Inohara et al., 1997, EMBO J. 16:1686-1694) (also known as neuronal death protein Dp5). This is a small protein of 92-residues that activates apoptosis. It contains a BH3 domain, but no BH1, BH2 or BH4 domains.

The following consensus patterns have been developed for the four BH domains:

g) Bromodomain (bromodomain). Some SEQ ID NOS represent polynucleotides encoding a polypeptide having a bromodomain region (Haynes et al., 1992, Nucleic Acids Res. 20:2693-2603, Tamkun et al., 1992, Cell 68:561-572, and Tamkun, 1995, Curr. Opin. Genet. Dev. 5:473-477), which is a conserved region of about 70 amino acids found in the following proteins: 1) Higher eukaryotes transcription initiation factor TFIID 250 Kd subunit (TBP-associated factor p250) (gene CCG1); P250 is associated with the TFIID TATA-box binding protein and seems essential for progression of the G1 phase of the cell cycle. 2) Human RING3, a protein of unknown function encoded in the MHC class II locus; 3) Mammalian CREB-binding protein (CBP), which mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein; 4) Mammalian homologs of brahma, including three brahma-like human: SNF2a(hBRM), SNF2b, and BRG1; 5) Human BS69, a protein that binds to adenovirus E1A and inhibits E1A transactivation; 6) Human peregrin (or Br140).

The bromodomain is thought to be involved in protein-protein interactions and may be important for the assembly or activity of multicomponent complexes involved in transcriptional activation.

h) Basic Region Plus Leucine Zipper Transcription Factors (BZIP). Some SEQ ID NOS, and thus the corresponding sequences these sequences validate, represent polynucleotides encoding a novel member of the family of basic region plus leucine zipper transcription factors. The bZIP superfamily (Hurst, Protein Prof. (11995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcription factors encompasses proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper required for dimerization. Members of the family include transcription factor AP-1, which binds selectively to enhancer elements in the cis control regions of SV40 and metallothionein IIA. AP-1, also known as c-jun, is the cellular homolog of the avian sarcoma virus 17 (ASV17) oncogene v-jun.

Other members of this protein family include jun-B and jun-D, probable transcription factors that are highly similar to jun/AP-1; the fos protein, a proto-oncogene that forms a non-covalent dimer with c-jun; the fos-related proteins fra-1, and fos B; and mammalian cAMP response element (CRE) binding proteins CREB, CREM, ATF-1, ATF-3, ATF-4, ATF-5, ATF-6 and LRF-1.

i) Cyclins (cyclin). Some SEQ ID NOS represent polynucleotides encoding cyclins, and SEQ ID NO:899 and 900, respectively, show the corresponding full-length polynucleotides. SEQ ID NO:901 and 902 show, respectively, the translations of SEQ ID NO:899 and 900. Cyclins (Nurse, 1990, Nature 344:503-508; Norbury et al., 1991, Curr. Biol. 1:23-24; and Lew et al., 1992, Trends Cell Biol. 2:77-81) are eukaryotic proteins that play an active role in controlling nuclear cell division cycles. There are two main groups of cyclins. G2/M cyclins are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). G1/S cyclins are essential for the control of the cell cycle at the G1/S (start) transition.

j) Eukaryotic thiol (cysteine) proteases active sites (Cys-protease). Some SEQ ID NOS, and thus also the sequences they validate, represent polynucleotides encoding proteins having a eukaryotic thiol (cysteine) protease active site. Eukaryotic thiol proteases (Dufour E., Biochimie (1988) 70:1335); are a family of proteolytic enzymes which contain an active site cysteine. Catalysis proceeds through a thioester intermediate and is facilitated by a nearby histidine side chain; an asparagine completes the essential catalytic triad. The proteases that belong to this family are: 1) vertebrate lysosomal cathepsins B (Kirschke H., et al., Protein Prof. (1995) 2:1587-1643); 2) vertebrate lysosomal dipeptidyl peptidase I (also known as cathepsin C) (Kirschke H., et al., supra); 3) vertebrate calpains (Calpains are intracellular calcium-activated thiol protease that contain both an N-terminal catalytic domain and a C-terminal calcium-binding domain); 4) mammalian cathepsin K, which seems involved in osteoclastic bone resorption (Shi G.-P., et al., FEBS Lett. (1995) 357:129); 5) human cathepsin O ([4] Velasco G., Ferrando A. A., Puente X. S., Sanchez L. M., Lopez-Otin C. J. Biol. Chem. (1994) 269:27136); 6) bleomycin hydrolase (which catalyzes the inactivation of the antitumor drug BLM (a glycopeptide)); 7) Plant enzymes such as: barley aleurain, EP-B1/B4; kidney bean EP-C1, rice bean SH-EP; kiwi fruit actinidin; papaya latex papin, chymopapain, caricain, and proteinase IV; pea turgor-responsive protein 15A; pineapple stem bromelain; rape COT44; rice oryzain alpha, beta, and gamma; tomato low-temperature induced, Arabidopsis thaliana A494, RD19A and RD21A; 8) House-dust mites allergens DerP1 and EurM1; 9) cathepsin B-like proteinases from the worms Caenorhabditis elegans (genes gcp-1, cpr-3, cpr-4, cpr-5 and cpr-6), Schistosoma mansoni (antigen SM31) and Japonica (antigen SJ31), Haemonchus contortus (genes AC-1 and AC-2), and Ostertagia ostertagi (CP-1 and CP-3); 10) slime mold cysteine proteinases CP1 and CP2; 11) cruzipain from Trypanosoma cruzi and brucei; 12) throphozoite cysteine proteinase (TCP) from various Plasmodium species; 13) proteases from Leishmania mexicana, Theileria annulata and Theileria parva; 14) Baculoviruses cathepsin-like enzyme (v-cath); 15) Drosophila small optic lobes protein (gene sol), a neuronal protein that contains a calpain-like domain; 16) yeast thiol protease BLH1/YCP1/LAP3; 17) Caenorhabditis elegans hypothetical protein C06G4.2, a calpain-like protein.

In addition, two bacterial peptidases are also part of this family: 1) aminopeptidase C from Lactococcus lactis (gene pepC) (Chapot-Chartier M. P., et al., Appl. Environ. Microbiol. (1993) 59:330); and 2) thiol protease tpr from Porphyromonas gingivalis. Three other proteins are structurally related to this family, but may have lost their proteolytic activity. These include: 1) soybean oil body protein P34 (which has its active site cysteine replaced by a glycine); 2) rat testin (which is a sertoli cell secretory protein highly similar to cathepsin L but with the active site cysteine is replaced by a serine); and 3) Plasmodium falciparum serine-repeat protein (SERA) (which is the major blood stage antigen and possesses a C-terminal thiol-protease-like domain (Higgins D. G., et al., Nature (1989) 340:604), with the active site cysteine is replaced by a serine).

k) Phorbol Esters/Diacylglycerol Binding (DAG_PE_bind). One SEQ represents a polynucleotide encoding a protein belonging to the family including phorbol esters/diacylglycerol binding proteins. Diacylglycerol (DAG) is an important second messenger. Phorbol esters (PE) are analogues of DAG and potent tumor promoters that cause a variety of physiological changes when administered to both cells and tissues. DAG activates a family of serine/threonine protein kinases, collectively known as protein kinase C (PKC) (Azzi et al., Eur. J. Biochem. (1992) 208:547). Phorbol esters can directly stimulate PKC. The N-terminal region of PKC, known as C1, has been shown (Ono et al., Proc. Natl. Acad. Sci. USA (1989) 86:4868) to bind PE and DAG in a phospholipid and zinc-dependent fashion. The C1 region contains one or two copies (depending on the isozyme of PKC) of a cysteine-rich domain about 50 amino-acid residues long and essential for DAG/PE-binding. Such a domain has also been found in, for example, the following proteins.

(1) Diacylglycerol kinase (EC 2.7.1.107) (DGK) (Sakane et al., Nature (1990) 344:345), the enzyme that converts DAG into phosphatidate. It contains two copies of the DAG/PE-binding domain in its N-terminal section. At least five different forms of DGK are known in mammals; and

(2) N-chimaerin, a brain specific protein which shows sequence similarities with the BCR protein at its C-terminal part and contains a single copy of the DAG/PE-binding domain at its N-terminal part. It has been shown (Ahmed et al., Biochem. J. (1990) 272:767, and Ahmed et al., Biochem. J. (1991) 280:233) to be able to bind phorbol esters.

The DAG/PE-binding domain binds two zinc ions; the ligands of these metal ions are probably the six cysteines and two histidines that are conserved in this domain. The signature pattern completely spans the DAG/PE domain.

l) DEAD and DEAH box families ATP-dependent helicases signatures (Dead_box_helic). Some SEQ ID NOS represent polynucleotides encoding a novel member of the DEAD box family. A number of eukaryotic and prokaryotic proteins have been characterized (Schmid S. R., et al., Mol. Microbiol. (1992) 6:283; Linder P., et al., Nature (1989) 337:121; Wassarman D. A., et al., Nature (1991) 349:463) on the basis of their structural similarity. All are involved in ATP-dependent, nucleic-acid unwinding. Proteins currently known to belong to this family are:

1) Initiation factor eIF-4A. Found in eukaryotes, this protein is a subunit of a high molecular weight complex involved in 5′cap recognition and the binding of mRNA to ribosomes. It is an ATP-dependent RNA-helicase.

2) PRP5 and PRP28. These yeast proteins are involved in various ATP-requiring steps of the pre-mRNA splicing process.

3) P110, a mouse protein expressed specifically during spermatogenesis.

4) An3, a Xenopus putative RNA helicase, closely related to P110.

5) SPP81/DED1 and DBP1, two yeast proteins involved in pre-mRNA splicing and related to P110.

6) Caenorhabditis elegans helicase glh-1.

7) MSS116, a yeast protein required for mitochondrial splicing.

8) SPB4, a yeast protein involved in the maturation of 25S ribosomal RNA.

9) p68, a human nuclear antigen. p68 has ATPase and DNA-helicase activities in vitro. It is involved in cell growth and division.

10) Rm62 (p62), a Drosophila putative RNA helicase related to p68.

11) DBP2, a yeast protein related to p68.

12) DHH1, a yeast protein.

13) DRS1, a yeast protein involved in ribosome assembly.

14) MAK5, a yeast protein involved in maintenance of dsRNA killer plasmid.

15) ROK1, a yeast protein.

16) ste13, a fission yeast protein.

17) Vasa, a Drosophila protein important for oocyte formation and specification of embryonic posterior structures.

18) Me31B, a Drosophila maternally expressed protein of unknown function.

19) dbpA, an Escherichia coli putative RNA helicase.

20) deaD, an Escherichia coli putative RNA helicase which can suppress a mutation in the rpsB gene for ribosomal protein S2.

21) rhlB, an Escherichia coli putative RNA helicase.

22) rhlE, an Escherichia coli putative RNA helicase.

23) rmB, an Escherichia coli protein that shows RNA-dependent ATPase activity, which interacts with 23S ribosomal RNA.

24) Caenorhabditis elegans hypothetical proteins T26G10.1, ZK512.2 and ZK686.2.

25) Yeast hypothetical protein YHR065c.

26) Yeast hypothetical protein YHR169w.

27) Fission yeast hypothetical protein SpAC31A2.07c.

28) Bacillus subtilis hypothetical protein yxiN.

All of the above proteins share a number of conserved sequence motifs. Some of them are specific to this family while others are shared by other ATP-binding proteins or by proteins belonging to the helicases ‘superfamily’ (Hodgman T. C., Nature (1988) 333:22 and Nature (1988) 333:578 (Errata); see worldwide web site at expasy.ch/www/linder/HELICASES_TEXT.html). One of these motifs, called the ‘D-E-A-D-box’, represents a special version of the B motif of ATP-binding proteins. Some other proteins belong to a subfamily which have His instead of the second Asp and are thus said to be ‘D-E-A-H-box’ proteins (Wassarman D. A., et al., Nature (1991) 349:463; Harosh I., et al., Nucleic Acids Res. (1991) 19:6331; Koonin E. V., et al., J. Gen. Virol. (1992) 73:989). Proteins currently known to belong to this DEAH subfamily are:

1) PRP2, PRP16, PRP22 and PRP43. These yeast proteins are all involved in various ATP-requiring steps of the pre-mRNA splicing process. 2) Fission yeast prh1, which my be involved in pre-mRNA splicing. 3) Male-less (mle), a Drosophila protein required in males, for dosage compensation of X chromosome linked genes. 4) RAD3 from yeast. RAD3 is a DNA helicase involved in excision repair of DNA damaged by UV light, bulky adducts or cross-linking agents. Fission yeast rad15 (rhp3) and mammalian DNA excision repair protein XPD (ERCC-2) are the homologs of RAD3. 5) Yeast CHL1 (or CTF1), which is important for chromosome transmission and normal cell cycle progression in G(2)/M. 6) Yeast TPS1. 7) Yeast hypothetical protein YKL078w. 8) Caenorhabditis elegans hypothetical proteins C06E1.10 and K03H1.2. 9) Poxviruses' early transcription factor 70 Kd subunit which acts with RNA polymerase to initiate transcription from early gene promoters. 10) I8, a putative vaccinia virus helicase. 11) hrpA, an Escherichia coli putative RNA helicase.

m) EF Hand (EFhand). Several of the validation sequences, and thus the sequences they validate, correspond to polynucleotides encoding a novel protein in the family of EF-hand proteins. Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand (Kawasaki et al., Protein. Prof. (1995) 2:305-490). This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).

Proteins known to contain EF-hand regions include: Calmodulin (Ca=4, except in yeast where Ca=3) (“Ca=” indicates approximate number of EF-hand regions); diacylglycerol kinase (EC 2.7.1.107) (DGK) (Ca=2); 2) FAD-dependent glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) from mammals (Ca=1); guanylate cyclase activating protein (GCAP) (Ca=3); MIF related proteins 8 (MRP-8 or CFAG) and 14 (MRP-14) (Ca=2); myosin regulatory light chains (Ca=1); oncomodulin (Ca=2); osteonectin (basement membrane protein BM-40) (SPARC); and proteins that contain an “osteonectin” domain (QR1, matrix glycoprotein SC1).

n) Ets Domain (Ets_Nterm). One SEQ ID NO, and thus the sequence it validates, represents a polynucleotide encoding a polypeptide with N-terminal homology in ETS domain. Proteins of this family contain a conserved domain, the “ETS-domain,” that is involved in DNA binding. The domain appears to recognize purine-rich sequences; it is about 85 to 90 amino acids in length, and is rich in aromatic and positively charged residues (Wasylyk, et al., Eur. J. Biochem. (1993) 211:718).

The ets gene family encodes a novel class of DNA-binding proteins, each of which binds a specific DNA sequence. These proteins comprise an ets domain that specifically interacts with sequences containing the common core tri-nucleotide sequence GGA. In addition to an ets domain, native ets proteins comprise other sequences which can modulate the biological specificity of the protein. Ets genes and proteins are involved in a variety of essential biological processes including cell growth, differentiation and development, and three members are implicated in oncogenic process.

o) Type II fibronectin collagen-binding domain (FntypeII). A few of the validation sequences, and thus the sequences they validate, represent polynucleotides encoding a polypeptide having a type II fibronectin collagen binding domain. Fibronectin is a plasma protein that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. The major part of the sequence of fibronectin consists of the repetition of three types of domains, which are called type I, II, and III (Skorstengaard K., et al., Eur. J. Biochem. (1986) 161:441). Type II domain is approximately forty residues long, contains four conserved cysteines involved in disulfide bonds and is part of the collagen-binding region of fibronectin. In fibronectin the type II domain is duplicated. Type II domains have also been found in the following proteins: 1) blood coagulation factor XII (Hageman factor) (1 copy); 2) bovine seminal plasma proteins PDC-109 (BSP-A1/A2) and BSP-A3 (Seidah N. G., et al., Biochem. J. (1987) 243:195. (twice); 3) cation-independent mannose-6-phosphate receptor (which is also the insulin-like growth factor II receptor) Kornfeld S., Annu. Rev. Biochem. (1992) 61:307) (1 copy); 4) Mannose receptor of macrophages (Taylor M. E., et al., J. Biol. Chem. (1990) 265:12156) (1 copy); 5) 180 Kd secretory phospholipase A2 receptor (1 copy) Lambeau G., et al., J. Biol. Chem. (1994) 269:1575; 6) DEC-205 receptor (1 copy); 6) Jiang W., et al., Nature (1995) 375:151); 7) 72 Kd type IV collagenase (EC 3.4.24.24) (MMP-2) (Collier I. E., et al., J. Biol. Chem. (1988) 263:6579) (3 copies); 7) 92 Kd type IV collagenase (EC 3.4.24.24) (MMP-9) (3 copies); 8) Hepatocyte growth factor activator (Miyazawa K., et al., J. Biol. Chem. (1993) 268:10024) (1 copy).

p) G-Protein Alpha Subunit (G-alpha). Several of the validation sequences, and thus the sequences they validate, correspond to a gene encoding a novel polypeptide of the G-protein alpha subunit family. Guanine nucleotide binding proteins (G-proteins) are a family of membrane-associated proteins that couple extracellularly-activated integral-membrane receptors to intracellular effectors, such as ion channels and enzymes that vary the concentration of second messenger molecules. G-proteins are composed of 3 subunits (alpha, beta and gamma) which, in the resting state, associate as a trimer at the inner face of the plasma membrane. The alpha subunit has a molecule of guanosine diphosphate (GDP) bound to it. Stimulation of the G-protein by an activated receptor leads to its exchange for GTP (guanosine triphosphate). This results in the separation of the alpha from the beta and gamma subunits, which always remain tightly associated as a dimer. Both the alpha and beta-gamma subunits are then able to interact with effectors, either individually or in a cooperative manner. The intrinsic GTPase activity of the alpha subunit hydrolyses the bound GTP to GDP. This returns the alpha subunit to its inactive conformation and allows it to reassociate with the beta-gamma subunit, thus restoring the system to its resting state.

G-protein alpha subunits are 350-400 amino acids in length and have molecular weights in the range 40-45 kDa. Seventeen distinct types of alpha subunit have been identified in mammals. These fall into 4 main groups on the basis of both sequence similarity and function: alpha-s, alpha-q, alpha-i and alpha-12 (Simon et al., Science (1993) 252:802). Many alpha subunits are substrates for ADP-ribosylation by cholera or pertussis toxins. They are often N-terminally acylated, usually with myristate and/or palmitoylate, and these fatty acid modifications are probably important for membrane association and high-affinity interactions with other proteins. The atomic structure of the alpha subunit of the G-protein involved in mammalian vision, transducin, has been elucidated in both GTP- and GDB-bound forms, and shows considerable similarity in both primary and tertiary structure in the nucleotide-binding regions to other guanine nucleotide binding proteins, such as p21-ras and EF-Tu.

q) Helicases conserved C-terminal domain (helicase C). Some SEQ ID NOS, and thus the sequences they validate, represent polynucleotides encoding novel members of the DEAD/H helicase family. The DEAD and DEAH families are described above.

r) Homeobox domain (homeobox). One SEQ ID NO, and thus the sequence it validates, represents a polynucleotide encoding a protein having a homeobox domain. The ‘homeobox’ is a protein domain of 60 amino acids (Gehring In: Guidebook to the Homebox Genes, Duboule D., Ed., pp 1-10, Oxford University Press, Oxford, (1994); Buerglin In: Guidebook to the Homebox Genes, pp 25-72, Oxford University Press, Oxford, (1994); Gehring Trends Biochem. Sci. (1992) 17:277-280; Gehring et al Annu. Rev. Genet. (1986) 20:147-173; Schofield Trends Neurosci. (1987) 10:3 6; see internet web site at copan.bioz.unibas.ch/homeo.html) first identified in number of Drosophila homeotic and segmentation proteins. It is extremely well conserved in many other animals, including vertebrates. This domain binds DNA through a helix-turn-helix type of structure. Several proteins that contain a homeobox domain play an important role in development. Most of these proteins are sequence-specific DNA-binding transcription factors. The homeobox domain is also very similar to a region of the yeast mating type proteins. These are sequence-specific DNA-binding proteins that act as master switches in yeast differentiation by controlling gene expression in a cell type-specific fashion.

A schematic representation of the homeobox domain is shown below. The helix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’ (for turn).

The pattern detects homeobox sequences 24 residues long and spans positions 34 to 57 of the homeobox domain.

x) MAP kinase kinase (mkk). Several validation sequences, and thus the sequences they validate, represent novel members of the MAP kinase kinase family. MAP kinases (MAPK) are involved in signal transduction, and are important in cell cycle and cell growth controls. The MAP kinase kinases (MAPKK) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKK regulation studies have led to the discovery of at least four MAPKK convergent pathways in higher organisms. One of these is similar to the yeast pheromone response pathway which includes the ste11 protein kinase. Two other pathways require the activation of either one or both of the serine/threonine kinase-encoded oncogenes c-Raf-1 and c-Mos. Additionally, several studies suggest a possible effect of the cell cycle control regulator cyclin-dependent kinase 1 (cdc2) on MAPKK activity. Finally, MAPKKs are apparently essential transducers through which signals must pass before reaching the nucleus. For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishida et al., Trends Biochem Sci (1993) 18:128-31; Ruderman Curr Opin Cell Biol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55; Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal (1996) 8:533-44.

y) 3′5′-cyclic nucleotide phosphodiesterases signature (PDEase). One SEQ ID NO, and thus the sequence it validates, represents a polynucleotide encoding a novel 3′5′-cyclic nucleotide phosphodiesterases (PDEases). PDEases catalyze the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5′ monophosphates (Charbonneau H., et al, Proc. Natl. Acad. Sci. U.S.A. (1986) 83:9308). There are at least seven different subfamilies of PDEases (Beavo J. A., et al., Trends Pharmacol. Sci. (1990) 11:150; see internet web site at weber.u.washington.edu/.about.pde/: 1) Type 1, calmodulin/calcium-dependent PDEases; 2) Type 2, cGMP-stimulated PDEases; 3) Type 3, cGMP-inhibited PDEases; 4) Type 4, cAMP-specific PDEases; 5) Type 5, cGMP-specific PDEases; 6) Type 6, rhodopsin-sensitive cGMP-specific PDEases; and 7) Type 7, High affinity cAMP-specific PDEases.

All PDEase forms share a conserved domain of about 270 residues.

z) Protein Kinase (protkinase). Several validation sequences, and thus the sequences they validate, represent polynucleotides encoding protein kinases. Protein kinases catalyze phosphorylation of proteins in a variety of pathways, and are implicated in cancer. Eukaryotic protein kinases (Hanks S. K., et al., FASEB J. (1995) 9:576; Hunter T., Meth. Enzymol. (1991) 200:3; Hanks S. K., et al., Meth. Enzymol. (1991) 200:38; Hanks S. K., Curr. Opin. Struct. Biol. (1991) 1:369; Hanks S. K., et al., Science (1988) 241:42) are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. Two of the conserved regions are the basis for the signature pattern in the protein kinase profile. The first region, which is located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. The second region, which is located in the central part of the catalytic domain, contains a conserved aspartic acid residue which is important for the catalytic activity of the enzyme (Knighton D. R., et al., Science (1991) 253:407). The protein kinase profile includes two signature patterns for this second region: one specific for serine/threonine kinases and the other for tyrosine kinases. A third profile is based on the alignment in (Hanks S. K., et al., FASEB J. (1995) 9:576) and covers the entire catalytic domain.

The protein kinase profile also detects receptor guanylate cyclases and 2-5A-dependent ribonucleases. Sequence similarities between these two families and the eukaryotic protein kinase family have been noticed previously. The profile also detects Arabidopsis thaliana kinase-like protein TMKL1 which seems to have lost its catalytic activity.

If a protein analyzed includes the two of the above protein kinase signatures, the probability of it being a protein kinase is close to 100%. Eukaryotic-type protein kinases have also been found in prokaryotes such as Myxococcus xanthus (Munoz-Dorado J., et al., Cell (1991) 67:995) and Yersinia pseudotuberculosis. The patterns shown above has been updated since their publication in (Bairoch A., et al., Nature (1988) 331:22).

aa) Ras family proteins (ras). One SEQ ID NO, and thus the sequence it validates, represent polynucleotides encoding the ras family of small GTP/GDP-binding proteins (Valencia et al., 1991, Biochemistry 30:4637-4648). Ras family members generally require a specific guanine nucleotide exchange factor (GEF) and a specific GTPase activating protein (GAP) as stimulators of overall GTPase activity. Among ras-related proteins, the highest degree of sequence conservation is found in four regions that are directly involved in guanine nucleotide binding. The first two constitute most of the phosphate and Mg2+ binding site (PM site) and are located in the first half of the G-domain. The other two regions are involved in guanosine binding and are located in the C-terminal half of the molecule. Motifs and conserved structural features of the ras-related proteins are described in Valencia et al., 1991, Biochemistry 30:4637-4648.

bb) Thioredoxin family active site (Thioredox). One SEQ ID NO, and thus the sequence it validates, represent a polynucleotide encoding a protein having a thioredoxin family active site. Thioredoxins (Holmgren A., Annu. Rev. Biochem. (1985) 54:237; Gleason F. K., et al., FEMS Microbiol. Rev. (1988) 54:271; Holmgren A. J. Biol. Chem. (1989) 264:13963; Eklund H., et al. Proteins (1991) 11:13) are small proteins of approximately one hundred amino-acid residues which participate in various redox reactions via the reversible oxidation of an active center disulfide bond. They exist in either a reduced form or an oxidized form where the two cysteine residues are linked in an intramolecular disulfide bond. Thioredoxin is present in prokaryotes and eukaryotes and the sequence around the redox-active disulfide bond is well conserved.

A number of eukaryotic proteins contain domains evolutionary related to thioredoxin, and all of them are protein disulphide isomerases (PDI). PDI (Freedman R. B., et al., Biochem. Soc. Trans. (1988) 16:96; Kivirikko K. I., et al., FASEB J. (1989) 3:1609; Freedman R. B., et al. Trends Biochem. Sci. (1994) 19:331) is an endoplasmic reticulum enzyme that catalyzes the rearrangement of disulfide bonds in various proteins. The various forms of PDI which are currently known are: 1) PDI major isozyme; a multifunctional protein that also function as the beta subunit of prolyl 4-hydroxylase (EC 1.14.11.2), as a component of oligosaccharyl transferase (EC 2.4.1.119), as thyroxine deiodinase, as glutathione-insulin transhydrogenase, and as a thyroid hormone-binding protein; 2) ERp60 (ER-60; 58 Kd microsomal protein), which is a protease; 3) ERp72; and 4) P5.

cc) TNFR/NGFR family cysteine-rich region (TNFR_c6). One SEQ ID NO, and thus the sequence it validates, represent a polynucleotide encoding a protein having a TNFR/NGFR family cysteine-rich region. A number of proteins, some of which are known to be receptors for growth factors, have been found to contain a cysteine-rich domain of about 110 to 160 amino acids in their N-terminal part, that can be subdivided into four (or in some cases, three) modules of about 40 residues containing 6 conserved cysteines. Proteins known to belong to this family (Mallet S., et al., Immunol. Today (1991) 12:220; Sprang S. R., Trends Biochem. Sci. (1990) 15:366; Krammer P. H., et al., Curr. Biol. (1992) 2:383; Bazan J. F., Curr. Biol. (1993) 3:603) are: 1) Tumor Necrosis Factor type I and type II receptors (TNFR) (Both receptors bind TNF-alpha and TNF-beta, but are only similar in the cysteine-rich region.); 2) Shope fibroma virus soluble TNF receptor (protein T2); 3) Lymphotoxin alpha/beta receptor; 4) Low-affinity nerve growth factor receptor (LA-NGFR); 5) CD40 (Bp50), the receptor for the CD40L (or TRAP) cytokine; 6) CD27, the receptor for the CD27L cytokine; 8) CD30, the receptor for the CD30L cytokine; 9) T-cell protein 4-1BB, the receptor for the 4-1BBL putative cytokine; 10) FAS antigen (or APO-1), the receptor for FASL, a protein involved in apoptosis (programmed cell death); 11) T-cell antigen OX40, the receptor for the OX40L cytokine; 12) Wsl-1, a receptor (for a yet undefined ligand) that mediates apoptosis; 13) Vaccinia virus protein A53 (SalF19R).

The six cysteines all involved in intrachain disulfide bonds (Banner D. W., et al, Cell (1993) 73:431). A schematic representation of the structure of the 40 residue module of these receptors is shown below:

where ‘C’ represents the conserved cysteine involved in a disulfide bond. The signature pattern for the cysteine-rich region is based mainly on the position of the six conserved cysteines in each of the repeats: Consensus pattern: C-x(4,6)-[FYH]-x(5,10)-C-x(0,2)-C-x(2,3)-C-x(7,11)-C-x(4,6)-[DNEQSKP]-x(2)-C (where the six C's are involved in disulfide bonds).

dd) Four Transmembrane Integral Membrane Proteins (transmembrane4). Several of the validation sequences, and thus the sequences they validate, correspond to a sequence encoding a polypeptide that is a member of the 4 transmembrane segments integral membrane protein family (transmembrane 4 family). The transmembrane 4 family of proteins includes a number of evolutionarily-related eukaryotic cell surface antigens (Levy et al., J. Biol. Chem., (1991) 266:14597; Tomlinson et al., Eur. J. Immunol. (1993) 23:136; Barclay et al. The leucocyte antigen factbooks. (1993) Academic Press, London/San Diego). The proteins belonging to this family include: 1) Mammalian antigen CD9 (MIC3), which is involved in platelet activation and aggregation; 2) Mammalian leukocyte antigen CD37, expressed on B lymphocytes; 3) Mammalian leukocyte antigen CD53 (OX-44), which is implicated in growth regulation in hematopoietic cells; 4) Mammalian lysosomal membrane protein CD63 (melanoma-associated antigen ME491; antigen AD1); 5) Mammalian antigen CD81 (cell surface protein TAPA-1), which is implicated in regulation of lymphoma cell growth; 6) Mammalian antigen CD82 (protein R2; antigen C33; Kangai 1 (KAI1)), which associates with CD4 or CD8 and delivers costimulatory signals for the TCR/CD3 pathway; 7) Mammalian antigen CD151 (SFA-1; platelet-endothelial tetraspan antigen 3 (PETA-3)); 8) Mammalian cell surface glycoprotein A15 (TALLA-1; MXS1); 9) Mammalian novel antigen 2 (NAG-2); 10) Human tumor-associated antigen CO-029; 11) Schistosoma mansoni and japonicum 23 Kd surface antigen (SM23/SJ23).

The members of the 4 transmembrane family share several characteristics. First, they all are apparently type III membrane proteins, which are integral membrane proteins containing an N-terminal membrane-anchoring domain which is not cleaved during biosynthesis and which functions both as a translocation signal and as a membrane anchor. The family members also contain three additional transmembrane regions, at least seven conserved cysteines residues, and are of approximately the same size (218 to 284 residues). These proteins are collectively know as the “transmembrane 4 superfamily” (TM4) because they span plasma membrane four times.

A schematic diagram of the domain structure of these proteins is as follows:

where Cyt is the cytoplasmic domain, TMa is the transmembrane anchor; TM2 to TM4 represents transmembrane regions 2 to 4, ‘C’ are conserved cysteines, and ‘*’ indicates the position of the consensus pattern. The consensus pattern spans a conserved region including two cysteines located in a short cytoplasmic loop between two transmembrane domains:

ee) Trypsin (trypsin). Some SEQ ID NOS, and thus the sequences they validate, correspond to novel serine proteases of the trypsin family. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved in this family of proteases (Brenner S., Nature (1988) 334:528). Proteases known to belong to the trypsin family include: 1) Acrosin; 2) Blood coagulation factors VII, IX, X, XI and XII, thrombin, plasminogen, and protein C; 3) Cathepsin G; 4) Chymotrypsins; 5) Complement components C1r, C1s, C2, and complement factors B, D and I; 6) Complement-activating component of RA-reactive factor; 7) Cytotoxic cell proteases (granzymes A to H); 8) Duodenase I; 9) Elastases 1, 2, 3A, 3B (protease E), leukocyte (medullasin); 10) Enterokinase (EC 3.4.21.9) (enteropeptidase); 11) Hepatocyte growth factor activator; 12) Hepsin; 13) Glandular (tissue) kallikreins (including EGF-binding protein types A, B, and C, NGF-gamma chain, gamma-renin, prostate specific antigen (PSA) and tonin); 14) Plasma kallikrein; 15) Mast cell proteases (MCP) 1 (chymase) to 8; 16) Myeloblastin (proteinase 3) (Wegener's autoantigen); 17) Plasminogen activators (urokinase-type, and tissue-type); 18) Trypsins I, II, III, and IV; 19) Tryptases; 20) Snake venom proteases such as ancrod, batroxobin, cerastobin, flavoxobin, and protein C activator; 21) Collagenase from common cattle grub and collagenolytic protease from Atlantic sand fiddler crab; 22) Apolipoprotein(a); 23) Blood fluke cercarial protease; 24) Drosophila trypsin like proteases: alpha, easter, snake-locus; 25) Drosophila protease stubble (gene sb); and 26) Major mite fecal allergen Der p III. All the above proteins belong to family S1 in the classification of peptidases (Rawlings N. D., et al., Meth. Enzymol. (1994) 244:19) and originate from eukaryotic species. It should be noted that bacterial proteases that belong to family S2A are similar enough in the regions of the active site residues that they can be picked up by the same patterns.

ff) WD Domain, G-Beta Repeats (WD_domain). A few of the validation sequences, and the sequences they validate, represent novel members of the WD domain/G-beta repeat family. Beta-transducin (G-beta) is one of the three subunits (alpha, beta, and gamma) of the guanine nucleotide-binding proteins (G proteins) which act as intermediaries in the transduction of signals generated by transmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds to and hydrolyzes GTP; the functions of the beta and gamma subunits are less clear but they seem to be required for the replacement of GDP by GTP as well as for membrane anchoring and receptor recognition.

In higher eukaryotes, G-beta exists as a small multigene family of highly conserved proteins of about 340 amino acid residues. Structurally, G-beta consists of eight tandem repeats of about 40 residues, each containing a central Trp-Asp motif (this type of repeat is sometimes called a WD-40 repeat). Such a repetitive segment has been shown to exist in a number of other proteins including: human LIS1, a neuronal protein involved in type-1 lissencephaly; and mammalian coatomer beta′ subunit (beta′-COP), a component of a cytosolic protein complex that reversibly associates with Golgi membranes to form vesicles that mediate biosynthetic protein transport.

gg) wnt Family of Developmental Signaling Proteins (Wnt_dev_sign). Several of the validation sequences, and thus the sequences they validate, correspond to novel members of the wnt family of developmental signaling proteins. Wnt-1 (previously known as int-1), the seminal member of this family, (Nusse R., Trends Genet. (1988) 4:291) is a proto-oncogene induced by the integration of the mouse mammary tumor virus. It is thought to play a role in intercellular communication and seems to be a signalling molecule important in the development of the central nervous system (CNS). The sequence of wnt-1 is highly conserved in mammals, fish, and amphibians. Wnt-1 was found to be a member of a large family of related proteins (Nusse R., et al., Cell (1992) 69:1073; McMahon A. P., Trends Genet. (1992) 8:1; Moon R. T., BioEssays (1993) 15:91) that are all thought to be developmental regulators. These proteins are known as wnt-2 (also known as irp), wnt-3, -3A, -4, -5A, -5B, -6, -7A, -7B, -8, -8B, -9 and -10. At least four members of this family are present in Drosophila; one of them, wingless (wg), is implicated in segmentation polarity.

All these proteins share the following features characteristics of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines that are probably involved in disulfide bonds. The Wnt proteins seem to adhere to the plasma membrane of the secreting cells and are therefore likely to signal over only few cell diameters. All sequences known to belong to this family are detected by the provided consensus pattern.

hh) Protein Tyrosine Phosphatase (Y_phosphatase). Several of the validation sequences, and thus the sequences they validate, represent a polynucleotide encoding a protein tyrosine kinase. Tyrosine specific protein phosphatases (EC 3.1.3.48) (PTPase) (Fischer et al., Science (1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463; Trowbridge, J. Biol. Chem. (1991) 266:23517; Tonks et al., Trends Biochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013) catalyze the removal of a phosphate group attached to a tyrosine residue. These enzymes are very important in the control of cell growth, proliferation, differentiation and transformation. Multiple forms of PTPase have been characterized and can be classified into two categories: soluble PTPases and transmembrane receptor proteins that contain PTPase domain(s).

Soluble PTPases include PTPN3 (H1) and PTPN4 (MEG), enzymes that contain an N-terminal band 4.1-like domain and could act at junctions between the membrane and cytoskeleton; PTPN6 (PTP-1C; HCP; SHP) and PTPN11 (PTP-2C; SH-PTP3; Syp), enzymes that contain two copies of the SH2 domain at its N-terminal extremity.

Dual specificity PTPases include DUSP1 (PTPN10; MAP kinase phosphatase-1; MKP-1) which dephosphorylates MAP kinase on both Thr-183 and Tyr-185; and DUSP2 (PAC-1), a nuclear enzyme that dephosphorylates MAP kinases ERK1 and ERK2 on both Thr and Tyr residues.

Structurally, all known receptor PTPases are made up of a variable length extracellular domain, followed by a transmembrane region and a C-terminal catalytic cytoplasmic domain. Some of the receptor PTPases contain fibronectin type III (FN-III) repeats, immunoglobulin-like domains, MAM domains or carbonic anhydrase-like domains in their extracellular region. The cytoplasmic region generally contains two copies of the PTPAse domain. The first seems to have enzymatic activity, while the second is inactive but seems to affect substrate specificity of the first. In these domains, the catalytic cysteine is generally conserved but some other, presumably important, residues are not.

PTPase domains consist of about 300 amino acids. There are two conserved cysteines and the second one has been shown to be absolutely required for activity. Furthermore, a number of conserved residues in its immediate vicinity have also been shown to be important.

ii) Zinc Finger, C2H2 Type (Zincfing_C2H2). Several of the validation sequences, and thus the sequences they validate, correspond to polynucleotides encoding novel members of the of the C2H2 type zinc finger protein family. Zinc finger domains (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99) are nucleic acid-binding protein structures first identified in the Xenopus transcription factor TFIIIA. These domains have since been found in numerous nucleic acid-binding proteins. A zinc finger domain is composed of 25 to 30 amino acid residues. Two cysteine or histidine residues are positioned at both extremities of the domain, which are involved in the tetrahedral coordination of a zinc atom. It has been proposed that such a domain interacts with about five nucleotides.

Many classes of zinc fingers are characterized according to the number and positions of the histidine and cysteine residues involved in the zinc atom coordination. In the first class to be characterized, called C2H2, the first pair of zinc coordinating residues are cysteines, while the second pair are histidines. A number of experimental reports have demonstrated the zinc-dependent DNA or RNA binding property of some members of this class.

Mammalian proteins having a C2H2 zipper include (number in parenthesis indicates number of zinc finger regions in the protein): basonuclin (6), BCL-6/LAZ-3 (6), erythroid krueppel-like transcription factor (3), transcription factors Sp1 (3), Sp2 (3), Sp3 (3) and Sp(4) 3, transcriptional repressor YY1 (4), Wilms' tumor protein (4), EGR1/Krox24 (3), EGR2/Krox20 (3), EGR3/Pilot (3), EGR4/AT133 (4), Evi-1 (10), GLI1 (5), GLI2 (4+), GLI3 (3+), HIV-EP1/ZNF40 (4), HIV-EP2 (2), KR1 (9+), KR2 (9), KR3 (15+), KR4 (14+), KR5 (11+), HF.12 (6+), REX-1 (4), ZfX (13), ZfY (13), Zfp-35 (18), ZNF7 (15), ZNF8 (7), ZNF35 (10), ZNF42/MZF-1 (13), ZNF43 (22), ZNF46/Kup (2), ZNF76 (7), ZNF91 (36), ZNF133 (3).

In addition to the conserved zinc ligand residues, it has been shown that a number of other positions are also important for the structural integrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved position is found four residues after the second cysteine; it is generally an aromatic or aliphatic residue. The consensus pattern for C2H2 zinc fingers is: C-x(2,4)-C-x(3)-[LIVMFYWC]-x(8)-H-x(3,5)-H. The two C's and two H's are zinc ligands.

jj) Zinc finger C3HC4 type (RING finger), signature (Zincfing_C3H4). Some SEQ ID NOS, and thus the sequences they validate, represent polynucleotides encoding a polypeptide having a C3HC4 type zinc finger signature. A number of eukaryotic and viral proteins contain this signature, which is primarily a conserved cysteine-rich domain of 40 to 60 residues (Borden K. L. B., et al., Curr. Opin. Struct. Biol. (1996) 6:395) that binds two atoms of zinc, and is probably involved in mediating protein-protein interactions. The 3D structure of the zinc ligation system is unique to the RING domain and is referred to as the “cross-brace” motif.

1) Mammalian V(D)J recombination activating protein (RAG1). RAG1 activates the rearrangement of immunoglobulin and T-cell receptor genes.

2) Mouse rpt-1. Rpt-1 is a trans-acting factor that regulates gene expression directed by the promoter region of the interleukin-2 receptor alpha chain or the LTR promoter region of HIV-1.

3) Human rip. Rfp is a developmentally regulated protein that may function in male germ cell development. Recombination of the N-terminal section of rfp with a protein tyrosine kinase produces the ret transforming protein.

4) Human 52 Kd Ro/SS-A protein. A protein of unknown function from the Ro/SS-A ribonucleoprotein complex. Sera from patients with systemic lupus erythematosus or primary Sjogren's syndrome often contain antibodies that react with the Ro proteins.

5) Human histocompatibility locus protein RING1.

6) Human PML, a probable transcription factor. Chromosomal translocation of PML with retinoic receptor alpha creates a fusion protein which is the cause of acute promyelocytic leukemia (APL).

7) Mammalian breast cancer type 1 susceptibility protein (BRCA1) ([E1] see Internet website at bioinformatics.weizmann.ac.il/hotmolecbase/entries/brca1.htm-).

8) Mammalian cbl proto-oncogene.

9) Mammalian bmi-1 proto-oncogene.

10) Vertebrate CDK-activating kinase (CAK) assembly factor MAT1, a protein that stabilizes the complex between the CDK7 kinase and cyclin H (MAT1 stands for ‘Menage A Trois’).

11) Mammalian mel-18 protein. Mel-18 which is expressed in a variety of tumor cells is a transcriptional repressor that recognizes and bind a specific DNA sequence.

12) Mammalian peroxisome assembly factor-1 (PAF-1) (PMP35), which is somewhat involved in the biogenesis of peroxisomes. In humans, defects in PAF-1 are responsible for a form of Zellweger syndrome, an autosomal recessive disorder associated with peroxisomal deficiencies.

13) Human MAT1 protein, which interacts with the CDK7-cyclin H complex.

14) Human RING1 protein.

15) Xenopus XNF7 protein, a probable transcription factor.

16) Trypanosoma protein ESAG-8 (T-LR), which may be involved in the postranscriptional regulation of genes in VSG expression sites or may interact with adenylate cyclase to regulate its activity.

17) Drosophila proteins Posterior Sex Combs (Psc) and Suppressor two of zeste (Su(z)2). The two proteins belong to the Polycomb group of genes needed to maintain the segment-specific repression of homeotic selector genes.

18) Drosophila protein male-specific msl-2, a DNA-binding protein which is involved in X chromosome dosage compensation (the elevation of transcription of the male single X chromosome).

19) Arabidopsis thaliana protein COP1 which is involved in the regulation of photomorphogenesis.

20) Fungal DNA repair proteins RAD5, RAD16, RAD 18 and rad8.

21) Herpesviruses trans-acting transcriptional protein ICP0/IE110. This protein which has been characterized in many different herpesviruses is a trans-activator and/or -repressor of the expression of many viral and cellular promoters.

22) Baculoviruses protein CG30.

23) Baculoviruses major immediate early protein (PE-38).

24) Baculoviruses immediate-early regulatory protein IE-N/IE-2.

25) Caenorhabditis elegans hypothetical proteins F54G8.4, R05D3.4 and T02C1.1.

26) Yeast hypothetical proteins YER116c and YKR017c.

The signature pattern for the C3HC4 finger is based on the central region of the domain:

Example 17 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 20 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 20 Description of cDNA Libraries Number of Library Clones in this (lib #) Description Clustering 1 Km12 L4 307133 Human Colon Cell Line, High Metastatic Potential (derived from Km12C) “High Colon” 2 Km12C 284755 Human Colon Cell Line, Low Metastatic Potential “Low Colon” 3 MDA-MB-231 326937 Human Breast Cancer Cell Line, High Metastatic Potential; micro- metastases in lung “High Breast” 4 MCF7 318979 Human Breast Cancer Cell, Non Metastatic “Low Breast” 8 MV-522 223620 Human Lung Cancer Cell Line, High Metastatic Potential “High Lung” 9 UCP-3 312503 Human Lung Cancer Cell Line, Low Metastatic Potential “Low Lung” 12 Human microvascular endothelial cells (HMEC) - Untreated 41938 PCR (OligodT) cDNA library 13 Human microvascular endothelial cells (HMEC) - Basic fibroblast 42100 growth factor (bFGF) treated PCR (OligodT) cDNA library 14 Human microvascular endothelial cells (HMEC) - Vascular endothelial 42825 growth factor (VEGF) treated PCR (OligodT) cDNA library 15 Normal Colon - UC#2 Patient 34285 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 16 Colon Tumor - UC#2 Patient 35625 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 17 Liver Metastasis from Colon Tumor of UC#2 Patient 36984 PCR (OligodT) cDNA library “High Colon Metastasis Tissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 19 Colon Tumor - UC#3 Patient 41388 PCR (OligodT) cDNA library “High Colon Tumor Tissue” 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 PCR (OligodT) cDNA library “High Colon Metastasis Tissue”

The KM12L4 and KM12C cell lines are described in Example 14 above. The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with 20 ng/ml BEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974).

Example 18 Polynucleotides Differentially Expressed in High Metastatic Potential Breast Cancer Cells Versus Low Metastatic Breast Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential breast cancer tissue and low metastatic breast cancer cells. Expression of these sequences in breast cancer can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest. The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential breast cancer cells and low metastatic potential breast cancer cells.

TABLE 21 Differentially expressed polynucleotides: Higher expression in high metastatic potential breast cancer (lib3) relative to low metastatic breast cancer cells (lib4) SEQ ID Cluster Lib3 Lib4 NOS: Sequence Name ID clones clones lib3/lib4 Zscore 889 RTA00000197AR.f.12.1 3513 17 5 3.317240 2.287632 990 RTA00000185AF.a.19.2 5749 9 0 8.780930 2.629923 998 RTA00000196F.e.7.1 1039 10 2 4.878294 1.978215 1003 RTA00000182AF.1.12.1 1027 41 17 2.353059 2.926571 1009 RTA00000192AF.g.23.1 6455 6 0 5.853953 2.011224 1018 RTA00000181AF.e.22.3 3442 17 4 4.146550 2.562391 1027 RTA00000198AF.c.17.1 6923 6 0 5.853953 2.011224 1208 RTA00000187AF.g.13.1 2991 10 1 9.756589 2.371428 1210 RTA00000192AF.o.19.1 3549 10 1 9.756589 2.371428 1231 RTA00000191AF.j.14.1 1002 42 20 2.048883 2.570309 1340 RTA00000190AF.p.3.1 2378 34 0 33.17240 5.588184 1354 RTA00000178AF.n.23.1 3298 12 1 11.70790 2.729313 1356 RTA00000191AF.c.3.1 3549 10 1 9.756589 2.371428 1373 RTA00000178AF.b.13.1 3114 9 1 8.780930 2.174815 1404 RTA00000184AF.i.23.3 1577 25 3 8.130490 3.903813 1450 RTA00000179AR.e.01.4 2493 33 9 3.577416 3.469507 1488 RTA00000197F.i.12.1 3605 14 1 13.65922 3.050936 1490 RTA00000186AF.d.24.1 3114 9 1 8.780930 2.174815 1598 RTA00000187AF.1.11.1 4482 14 3 4.553074 2.374769 1719 RTA00000401F.m.02.1 1573 34 7 4.738914 3.982056 1746 RTA00000422F.c.02.1 2902 18 5 3.512372 2.443314 1765 RTA00000418F.m.19.1 8890 6 0 5.853953 2.011224 1786 RTA00000351R.g.11.1 3077 17 4 4.146550 2.562391 1939 RTA00000408F.1.13.1 4423 12 1 11.70790 2.729313 1948 RTA00000404F.m.10.2 779 60 22 2.660887 3.974953 1975 RTA00000400F.k.22.1 2512 7 0 6.829612 2.235371 2014 RTA00000340R.f.05.1 3202 18 3 5.853953 2.998867 2028 RTA00000422F.c.17.1 1360 26 11 2.306102 2.226876 2049 RTA00000118A.a.23.1 3500 12 3 3.902635 2.018050 2198 RTA00000401F.k.14.1 211 121 43 2.745458 5.856098 2968 RTA00000191AF.j.14.1 1002 42 20 2.048883 2.570309 2379 RTA00000405F.l.11.1 2055 29 8 3.536763 3.213373 2595 RTA00000423F.j.03.1 5391 6 0 5.853953 2.011224 2608 RTA00000399F.o.24.1 2272 17 1 16.58620 3.483575 2621 RTA00000401F.j.15.1 3061 14 0 13.65922 3.428594 2639 RTA00000348R.o.12.1 2263 6 0 5.853953 2.011224 2713 RTA00000340F.f.22.1 1720 57 8 6.951569 5.855075 2726 RTA00000401F.g.22.1 1147 28 12 2.276537 2.294031 2734 RTA00000346F.o.16.1 176 170 44 3.769591 8.366611 2759 RTA00000400F.g.02.1 1508 21 5 4.097767 2.879196 2884 RTA00000527F.j.02.2 4896 11 0 10.73224 2.974502 2903 RTA00000528F.i.22.1 2478 17 5 3.317240 2.287632 3067 RTA00000528F.j.11.1 1070 26 6 4.227855 3.289393 3089 RTA00000527F.k.09.1 213 17 4 4.146550 2.562391 3144 RTA00000528F.b.03.1 2078 11 2 5.366124 2.174565 3169 RTA00000525F.d.13.1 349 77 1 75.12573 8.384408 3306 RTA00000528F.g.22.2 920 76 32 2.317189 4.010278 3332 RTA00000528F.h.02.2 1701 18 4 4.390465 2.714073 3336 RTA00000528F.c.11.1 1701 18 4 4.390465 2.714073

TABLE 22 Differentially expressed polynucleotides: Higher expression in low metastatic breast cancer cells (lib4) relative to high metastatic potential breast cancer (lib3) SEQ ID Lib4 Lib 3 NOS: Sequence Name Cluster ID Clones Clones lib4/lib3 Zscore 859 RTA00000177AR.n.8.1 4188 4 13 3.33108 1.99126 880 RTA00000181AF.p.4.3 40392 1 8 8.19958 2.03713 888 RTA00000199F.f.08.2 12445 0 11 11.2744 3.05623 933 RTA00000177AF.n.8.3 4188 4 13 3.33108 1.99126 1016 RTA00000186AF.p.09.2 6879 3 43 14.6909 5.83444 1047 RTA00000201F.d.09.1 1827 37 157 4.34910 8.71727 1105 RTA00000192AF.a.24.1 13183 0 7 7.17463 2.30057 1263 RTA00000182AF.j.20.1 4769 2 20 10.2494 3.68254 1264 RTA00000181AF.c.11.1 4769 2 20 10.2494 3.68254 1347 RTA00000197AF.k.9.1 3138 1 10 10.2494 2.45316 1396 RTA00000193AF.b.24.1 35 386 1967 5.22298 33.2328 1408 RTA00000200AF.g.18.1 1600 0 23 23.5738 4.64683 1414 RTA00000183AF.a.19.2 3788 0 6 6.14969 2.07158 1434 RTA00000190AF.d.2.1 2444 26 55 2.16815 3.22244 1537 RTA00000198F.m.12.1 4 987 2807 2.91492 30.3819 1551 RTA00000179AF.p.15.1 5622 2 13 6.66216 2.62993 1555 RTA00000198F.i.2.1 8076 0 9 9.22453 2.70385 1570 RTA00000200R.f.10.1 4 987 2807 2.91492 30.3819 1590 RTA00000178AF.i.01.2 4 987 2807 2.91492 30.3819 1600 RTA00000404F.a.02.1 9738 1 13 13.3243 2.98623 1834 RTA00000126A.o.23.1 6268 3 18 6.14969 3.11179 1966 RTA00000401F.o.06.1 2679 4 23 5.89345 3.52846 1986 RTA00000411F.a.15.1 73812 0 12 12.2993 3.21838 2130 RTA00000345F.n.12.1 7337 3 16 5.46639 2.80694 2133 RTA00000126A.g.7.1 1902 13 48 3.78442 4.45002 2279 RTA00000345F.e.11.1 4392 1 8 8.19958 2.03713 2704 RTA00000340F.p.18.1 287 6 173 29.5526 12.5749 2777 RTA00000400F.f.11.1 4088 0 82 84.0457 9.05778 2778 RTA00000341F.o.12.1 2883 9 21 2.39154 2.07600 2823 RTA00000122A.h.24.1 48 412 1020 2.53749 16.5262 2824 RTA00000346F.j.13.1 5337 5 17 3.48482 2.40321 2851 RTA00000400F.g.08.1 1275 15 32 2.18655 2.41857 2867 RTA00000523F.d.19.1 26489 1 8 8.19958 2.03713 3253 RTA00000526F.d.17.1 2757 4 16 4.09979 2.51500 2064 RTA00000528F.d.04.1 2395 12 37 3.16025 3.51521

Example 19 Polynucleotides Differentially Expressed in High Metastatic Potential Lung Cancer Cells Versus Low Metastatic Lung Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential lung cancer tissue and low metastatic lung cancer cells. Expression of these sequences in lung cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells are associated can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential lung cancer cells and low metastatic potential lung cancer cells:

TABLE 23 Differentially expressed polynucleotides: Higher expression in high metastatic potential lung cancer cells (lib8) relative to low metastatic lung cancer cells (lib9) SEQ ID Lib8 Lib9 NO: Sequence Name Cluster ID clones clones lib8/lib9 Zscore 854 RTA00000198AF.n.16.1 3721 9 0 12.5772 3.20845 898 RTA00000200F.o.22.1 983 8 1 11.1797 2.53243 909 RTA00000198AF.m.16.1 51 348 66 7.36849 17.4315 1015 RTA00000198R.c.07.1 19181 6 0 8.38484 2.48169 1047 RTA00000201F.d.09.1 1827 45 15 4.19242 5.09891 1096 RTA00000181AF.e.18.3 8 1355 122 15.5211 39.0214 1097 RTA00000181AF.e.17.3 8 1355 122 15.5211 39.0214 1129 RTA00000181AR.j.14.3 5399 12 0 16.7696 3.80239 1263 RTA00000182AF.j.20.1 4769 10 3 4.65824 2.29362 1264 RTA00000181AF.c.11.1 4769 10 3 4.65824 2.29362 1335 RTA00000196F.k.11.1 3 986 392 3.51507 22.4683 1369 RTA00000198AF.c.7.1 19181 6 0 8.38484 2.48169 1370 RTA00000185AF.e.20.1 5865 12 0 16.7696 3.80239 1396 RTA00000193AF.b.24.1 35 868 11 110.273 34.2897 1537 RTA00000198F.m.12.1 4 506 209 3.38335 15.7309 1544 RTA00000183AF.i.18.2 40129 7 0 9.78231 2.74441 1570 RTA00000200R.f.10.1 4 506 209 3.38335 15.7309 1586 RTA00000177AF.m.1.1 14929 23 16 2.00886 2.02420 1590 RTA00000178AF.i.01.2 4 506 209 3.38335 15.7309 1705 RTA00000339F.f.11.1 5832 5 0 6.98736 2.18988 1834 RTA00000126A.o.23.1 6268 5 0 6.98736 2.18988 1932 RTA00000399F.f.11.1 40167 8 0 11.1797 2.98512 2132 RTA00000423F.e.11.1 2566 11 2 7.68610 2.85611 2261 RTA00000339F.o.07.1 2566 11 2 7.68610 2.85611 2288 RTA00000419F.p.03.1 1937 10 3 4.65824 2.29362 2298 RTA00000340F.1.05.1 38935 7 0 9.78231 2.74441 2414 RTA00000403F.a.17.1 13686 8 0 11.1797 2.98512 2441 RTA00000401F.n.23.1 1552 8 1 11.1797 2.53243 2823 RTA00000122A.h.24.1 48 342 155 3.08345 12.2138 2868 RTA00000528F.b.23.1 1605 22 4 7.68610 4.23808 2878 RTA00000528F.m.16.1 4468 6 1 8.38484 1.97787 2970 RTA00000526F.d.01.1 4468 6 1 8.38484 1.97787

TABLE 24 Differentially expressed polynucleotides: Higher expression in low metastatic lung cancer cells (lib9) relative to high metastatic potntial lung cancer cells SEQ ID Cluster Lib8 Lib9 NO: Sequence Name ID clones clones lib9/lib8 Zscore 1018 RTA00000181AF.e.22.3 3442 5 23 3.291654 2.368262 1098 RTA00000178AF.n.2.1 17083 0 8 5.724617 2.034117 1310 RTA00000177AF.p.20.1 4141 4 27 4.830145 3.070829 1415 RTA00000198AF.b.14.1 801 16 46 2.057284 2.411087 1418 RTA00000192AF.f.3.1 5257 5 25 3.577885 2.596857 1434 RTA00000190AF.d.2.1 2444 12 37 2.206362 2.299984 1766 RTA00000399F.1.14.1 3354 5 20 2.862308 1.998763 2199 RTA00000406F.m.04.1 14959 11 41 2.667151 2.865855 2266 RTA00000405F.h.07.2 4984 3 16 3.816411 2.058861 2851 RTA00000400F.g.08.1 1275 10 42 3.005423 3.147111 2882 RTA00000527F.p.06.1 1292 8 33 2.951755 2.724411 3089 RTA00000527F.k.09.1 213 137 403 2.104945 7.661033

Example 20 Polynucleotides Differentially Expressed in High Metastatic Potential Colon Cancer Cells Versus Low Metastatic Colon Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential colon cancer tissue and low metastatic colon cancer cells. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides with differential expression between high metastatic potential colon cancer cells and low metastatic potential colon cancer cells:

TABLE 25 Differentially expressed polynucleotides: Higher expression in high metastatic potential colon cancer (lib1) relative to low metastatic colon cancer cells (lib2) SEQ ID Lib1 Lib2 NO: Sequence Name Cluster ID clones clones lib1/lib2 Zscore 1072 RTA00000187AR.h.15.2 6660 7 0 6.489973399 2.169320547 1124 RTA00000193AF.b.18.1 7542 8 0 7.417112456 2.36964728 1199 RTA00000184AR.b.24.1 5777 9 1 8.344251513 2.09555146 1335 RTA00000196F.k.11.1 3 5268 2164 2.257009497 32.96556438 1447 RTA00000183AR.d.11.3 6420 8 0 7.417112456 2.36964728 1524 RTA00000177AF.f.10.1 6420 8 0 7.417112456 2.36964728 1596 RTA00000192AF.o.7.1 5275 11 2 5.099264814 2.083995588 1597 RTA00000192AF.o.17.1 5275 11 2 5.099264814 2.083995588 2085 RTA00000346F.1.13.1 7542 8 0 7.417112456 2.36964728 2108 RTA00000349R.g.10.1 5777 9 1 8.344251513 2.09555146 2245 RTA00000421F.m.14.1 3524 21 6 3.2449867 2.499690198 2286 RTA00000350R.g.10.1 9026 7 0 6.489973399 2.169320547 2358 RTA00000399F.o.06.1 13574 7 0 6.489973399 2.169320547 2695 RTA00000421F.a.06.1 2385 27 4 6.258188635 3.743586088 2759 RTA00000400F.g.02.1 1508 46 17 2.508729213 3.230059264 2868 RTA00000528F.b.23.1 1605 36 11 3.034273278 3.244010467 2910 RTA00000528F.m.12.1 5768 12 0 3.046665462

TABLE 26 Differentially expressed polynucleotides: Higher expression in low metastatic colon cancer cells (lib2)relative to high metastatic potential colon cancer (lib1) SEQ ID Cluster Lib2 NOS: Sequence Name ID Lib1 clones clones lib2/lib1 Zscore 877 RTA00000178AR.a.20.1 945 9 21 2.51670 2.21703 1094 RTA00000192AF.j.21.1 2289 3 23 8.26916 3.92187 1126 RTA00000193AF.c.15.1 3726 3 14 5.03340 2.58312 1214 RTA00000179AF.c.15.3 2995 4 13 3.50540 2.09770 1231 RTA00000191AF.j.14.1 1002 12 65 5.84234 6.26259 1287 RTA00000197AR.i.17.1 3516 5 17 3.66719 2.52439 1304 RTA00000179AF.c.15.1 2995 4 13 3.50540 2.09770 1389 RTA00000196F.a.2.1 3575 5 14 3.02004 2.00158 1404 RTA00000184AF.i.23.3 1577 12 40 3.59528 4.01991 1547 RTA00000198F.1.09.1 3611 2 13 7.01081 2.73040 1548 RTA00000190AF.o.12.1 3438 5 14 3.02004 2.00158 1939 RTA00000408F.1.13.1 4423 1 8 8.62869 2.11495 1948 RTA00000404F.m.10.2 779 27 54 2.15717 3.23169 2049 RTA00000118A.a.23.1 3500 3 13 4.67387 2.40298 2198 RTA00000401F.k.14.1 211 109 206 2.03843 6.08597 2231 RTA00000191AF.j.14.1 1002 12 65 5.84234 6.26259 2578 RTA00000345F.b.17.1 945 9 21 2.51670 2.21703 2586 RTA00000422F.b.22.1 2368 14 34 2.61942 3.00662 2798 RTA00000401F.j.23.1 570 59 148 2.70560 6.66631 3106 RTA00000527F.o.12.1 688 29 60 2.23155 3.53946 3169 RTA00000525F.d.13.1 349 69 138 2.15717 5.27497

Example 21 Polynucleotides Differentially Expressed in High Metastatic Potential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential colon cancer tissue and normal tissue. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells are associated can be indicative of increased expression of genes or regulatory sequences involved in the advanced disease state which involves processes such as angiogenesis, dedifferentiation, cell replication, and metastasis. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential colon cancer cells and normal colon cells:

TABLE 27 Differentially expressed polynucleotides isolated from samples from two patients (UC#2 and UC#3): Higher expression in high metastatic potential colon tissue (UC#2: lib17; UC#3: lib20) vs. normal colon tissue (UC#2: lib15; UC#3: lib18) SEQ ID Cluster lib17 NO: Sequence Name ID lib15 clones clones lib17/lib15 Zscore 909 RTA00000198AF.m.16.1 51 1 10 9.27022 2.28830 2624 RTA00000118A.j.24.1 18 4 23 5.33037 3.27028 2743 RTA00000345F.j.09.1 13 14 80 5.29727 6.34580 SEQ ID Cluster lib18 lib20 NO: Sequence Name ID clones clones lib20/lib18 Zscore 2743 RTA00000345F.j.09.1 13 12 23 2.24234 2.16077

TABLE 28 Differentially expressed polynucleotides isolated from samples from two patients (UC#2 and UC#3): Higher expression in normal colon tissue (UC#2: lib15; UC#3: lib18)vs. high metastatic potential colon tissue (UC#2: lib17; UC#3: lib20). SEQ ID Cluster Lib5 L1ib7 Z Score: NO: Sequence Name ID Clones Clones lib15/lib17 >2.5899%; >1.96 1335 RTA00000196F.k.11.1 3 242 26 10.04 13.78900072 SEQ ID Cluster Lib18 Lib20 NO: Sequence Name ID clones clones lib18/lib20 Zscore 1335 RTA00000196F.k.11.1 3 409 46 7.59993 15.3998

Example 22 Polynucleotides Differentially Expressed in High Colon Tumor Potential Patient Tissue Versus Metastasized Colon Cancer Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high tumor potential colon cancer tissue and cells derived from high metastatic potential colon cancer cells. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the transformation of precancerous tissue to malignant tissue. This information can be useful in the prevention of achieving the advanced malignant state in these tissues, and can be important in risk assessment for a patient.

The following table summarizes identified polynucleotides with differential expression between high tumor potential colon cancer tissue and cells derived from high metastatic potential colon cancer cells:

TABLE 29 Differentially expressed polynucleotides: High tumor potential colon tissue vs. metastatic colon tissue SEQ ID L19 L20 NO: Sequence Name Cluster ID clones clones lib19/lib20 Zscore 1096 RTA00000181AF.e.18.3 8 14 1 10.4712 2.56699 1097 RTA00000181AF.e.17.3 8 14 1 10.4712 2.56699 1335 RTA00000196F.k.11.1 3 328 46 5.33318 11.8962 1425 RTA00000191AF.p.3.2 17 24 2 8.97535 3.41950 1537 RTA00000198F.m.12.1 4 26 8 2.43082 2.09705 1570 RTA00000200R.f.10.1 4 26 8 2.43082 2.09705 1590 RTA00000178AF.i.01.2 4 26 8 2.43082 2.09705 2624 RTA00000118A.j.24.1 18 80 13 4.60274 5.51440 2743 RTA00000345F.j.09.1 13 148 23 4.81287 7.68618

Example 23 Polynucleotides Differentially Expressed in High Tumor Potential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high tumor potential colon cancer tissue and normal tissue. Expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. For example, sequences that are highly expressed in the potential colon cancer cells are associated with or can be indicative of increased expression of genes or regulatory sequences involved in early tumor progression. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential colon cancer cells and normal colon cells:

TABLE 30 Differentially expressed polynucleotides detected in samples from two patients (UC#2 and UC#3): Higher expression in tumor potential colon tissue (UC#2: lib16; UC#3: lib19)vs. normal colon tissue (UC#2: lib15; UC#3: lib18) SEQ ID Lib15 Lib16 NO: Sequence Name Cluster ID clones clones lib16/lib15 Zscore 2743 RTA00000345F.j.09.1 13 14 50 3.43709 4.22436 SEQ ID Cluster Lib18 Lib19 NO: Sequence Name ID clones clones lib19/lib18 Zscore 909 RTA00000198AF.m.16.1 51 0 14 12.2505 3.23250 1096 RTA00000181AF.e.18.3 8 1 14 12.2505 2.84687 1097 RTA00000181AF.e.17.3 8 1 14 12.2505 2.84687 1425 RTA00000191AF.p.3.2 17 4 24 5.25021 3.24580 1537 RTA00000198F.m.12.1 4 6 26 3.79182 2.98901 1560 RTA00000200F.p.05.1 3984 0 7 6.12525 2.09621 1570 RTA00000200R.f.10.1 4 6 26 3.79182 2.98901 1590 RTA00000178AF.i.01.2 4 6 26 3.79182 2.98901 2624 RTA00000118A.j.24.1 18 10 80 7.00028 6.65963 2743 RTA00000345F.j.09.1 13 12 148 10.7921 9.86174

TABLE 31 Differentially expressed polynucleotides: Higher expression in normal colon tissue (UC#2: lib15) vs. tumor potential colon tissue (UC#2: lib16) Lib15 Lib16 SEQ ID NO: Sequence Name Cluster ID clones clones lib15/lib16 Zscore 1335 RTA00000196F.k.11.1 3 242 39 6.44765 12.3988

Example 24 Polynucleotides Differentially Expressed in Growth Factor-Stimulated Human Microvascular Endothelial Cells (HMEC) Relative to Untreated HMEC

A number of polynucleotide sequences have been identified that are differentially expressed between human microvascular endothelial cells (HMEC) that have been treated with growth factors relative to untreated HMEC.

Sequences that are differentially expressed between growth factor-treated HMEC and untreated HMEC can represent sequences encoding gene products involved in angiogenesis, metastasis (cell migration), and other development and oncogenic processes. For example, sequences that are more highly expressed in HMEC treated with growth factors (such as bFGF or VEGF) relative to untreated HMEC can serve as markers of cancer cells of higher metastatic potential. Detection of expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The following table summarizes identified polynucleotides with differential expression between growth factor-treated and untreated HMEC.

TABLE 32 Differentially expressed polynucleotides: Higher expression in bFGF treated HMEC (lib13) vs. untreated HMEC (lib12) Lib12 Lib13 SEQ ID NO: Sequence Name Cluster ID clones clones lib13/lib12 Zscore 1492 RTA00000199F.i.9.1 7 25 52 2.07199 2.94741

TABLE 33 Differentially expressed polynucleotides: Higher expression in VEGF treated HMEC (lib14) vs. untreated HMEC (lib12) Cluster Lib12 Lib14 SEQ ID NO: Sequence Name ID clones clones lib14/lib12 Zscore 1492 RTA00000199F.i.9.1 7 25 67 2.62449 4.17666 2743 RTA00000345F.j.09.1 13 22 49 2.18114 2.99887

Example 25 Polynucleotides Differentially Expressed Across Multiple Libraries

A number of polynucleotide sequences have been identified that are differentially expressed between cancerous cells and normal cells across all three tissue types tested (i.e., breast, colon, and lung). Expression of these sequences in a tissue or any origin can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. These polynucleotides can also serve as non-tissue specific markers of, for example, risk of metastasis of a tumor. The following table summarizes identified polynucleotides that were differentially expressed but without tissue type-specificity in the breast, colon, and lung libraries tested.

TABLE 34 Polynucleotides Differentially Expressed Across Multiple Library Comparisons Cell or Tissue Sample and Cancer SEQ ID Clones in 1st Clones in 2nd State Compared NO. Cluster Lib Lib Ratio (Z Score) 2868 1605 lib1 lib2 lib1/lib2 colon: high met > low met 36 11 3.0342732 (3.2440104) lib8 lib9 lib8/lib9 lung: high met > low met 22 4 7.6861036 (4.2380835) 909 51 lib8 lib9 lib8/lib9 lung: high met > low met 348 66 7.3684960 (17.431560) lib18 lib19 lib19/lib18 pt #3 colon: tumor > normal 0 14 12.250507 (3.2325073) lib15 lib17 lib17/lib15 pt #2 colon: met > normal 1 10 9.2702249 (2.2883061) 1018 3442 lib8 lib9 lib9/lib8 lung: low met > high met 5 23 3.2916548 (2.3682625) lib3 lib4 lib3/lib4 breast: high met > low met 17 4 4.1465504 (2.5623912) 1047 1827 lib8 lib9 lib8/lib9 lung: high met > low met 45 15 4.1924201 (5.0989192) lib3 lib4 lib4/lib3 breast: low met > high met 37 157 4.3491051 (8.7172773) 3089 213 lib8 lib9 lib9/lib8 lung: low met > high met 137 403 2.1049458 (7.6610331) lib3 lib4 lib3/lib4 breast: high met > low met 17 4 4.1465504 (2.5623912) 1834 6268 lib8 lib9 lib8/lib9 lung: high met > low met 5 0 6.9873669 (2.1898837) lib3 lib4 lib4/lib3 breast: low met > high met 3 18 6.1496901 (3.1117967) 1096 8 lib8 lib9 lib8/lib9 lung: high met > low met 1355 122 15.521118 (39.021411) lib19 lib20 lib19/lib20 pt. #3 colon: tumor > met 14 1 10.471247 (2.5669948) lib18 lib19 lib19/lib18 pt #3 colon: tumor > normal 1 14 12.250507 (2.8468716) 1097 8 lib8 lib9 lib8/lib9 lung: high met > low met 1355 122 15.521118 (39.021411) lib19 lib20 lib19/lib20 pt. #3 colon: tumor > met 14 1 10.471247 (2.5669948) lib18 lib19 lib19/lib18 pt #3 colon: tumor > normal 1 14 12.250507 (2.8468716) 3169 349 lib3 lib4 lib3/lib4 breast: high met > low met 77 1 75.125736 (8.3844087) lib1 lib2 lib2/lib1 colon: low met > high met 69 138 2.1571737 (5.2749799) 1939 4423 lib3 lib4 lib3/lib4 breast: high met > low met 12 1 11.707907 (2.7293134) lib1 lib2 lib2/lib1 colon: low met > high met 1 8 8.6286948 (2.1149516) 1968 779 lib3 lib4 lib3/lib4 breast: high met > low met 60 22 2.6608879 (3.9749537) lib1 lib2 lib2/lib1 colon: low met > high met 27 54 2.1571737 (3.2316908) 1231 1002 lib3 lib4 lib3/lib4 breast: high met > low met 42 20 2.0488837 (2.5703094) lib1 lib2 lib2/lib1 colon: low met > high met 12 65 5.8423454 (6.2625969) 1263 4769 lib8 lib9 lib8/lib9 lung: high met > low met 10 3 4.6582446 (2.2936274) lib3 lib4 lib4/lib3 breast: low met > high met 2 20 10.249483 (3.6825426) 1264 4769 lib8 lib9 lib8/lib9 lung: high met > low met 10 3 4.6582446 (2.2936274) lib3 lib4 lib4/lib3 breast: low met > high met 2 20 10.249483 (3.6825426) 2049 3500 lib3 lib4 lib3/lib4 breast: high met > low met 12 3 3.9026356 (2.0180506) lib1 lib2 lib2/lib1 colon: low met > high met 3 13 4.6738763 (2.4029818) 1335 3 lib1 lib2 lib1/lib2 colon: high met > low met 5268 2164 2.2570094 (32.965564) lib8 lib9 lib8/lib9 lung: high met > low met 986 392 3.5150733 (22.468331) lib19 lib20 lib19/lib20 pt #3 colon: tumor > met 328 46 5.3331820 (11.896271) lib18 lib20 lib18/lib20 pt #3 colon: normal > met 409 46 7.5999342 (15.399861) lib15 lib17 lib15/lib17 pt#2 colon: normal > met 242 26 10.04 (13.789000) lib15 lib16 lib15/lib16 pt#2 colon: normal > tumor 242 39 6.44765 12.39883 1396 35 lib8 lib9 lib8/lib9 lung: high met > low met 868 11 110.27335 (34.289704) lib3 lib4 lib4/lib3 breast: low met > high met 386 1967 5.2229880 (33.232871) 1404 1577 lib3 lib4 lib3/lib4 breast: high met > low met 25 3 8.1304909 (3.9038139) lib1 lib2 lib2/lib1 colon: low met > high met 12 40 3.5952895 (4.0199130) 1425 17 lib19 lib20 lib19/lib20 pt #3 colon: tumor > met 24 2 8.9753551 (3.4195074) lib18 lib19 lib19/lib18 pt #3 colon: tumor > normal 4 24 5.2502174 (3.2458055) 1434 2444 lib3 lib4 lib4/lib3 breast: low met > high met 26 55 2.1681599 (3.2224421) lib8 lib9 lib9/lib8 lung: low met > high met 12 37 2.2063628 (2.2999846) 2198 211 lib3 lib4 lib3/lib4 breast: high met > low met 121 43 2.7454588 (5.8560985) lib1 lib2 lib2/lib1 colon: low met > high met 109 206 2.0384302 (6.0859794) 2231 1002 lib3 lib4 lib3/lib4 breast: high met > low met 42 20 2.0488837 (2.5703094) lib1 lib2 lib2/lib1 colon: low met > high met 12 65 5.8423454 (6.2625969) 1492 7 lib12 lib14 lib14/lib12 HMEC: VEGF > untreated 25 67 2.6244913 (4.1766696) lib12 lib13 lib13/lib12 HMEC: bFGF > untreated 25 52 2.0719962 (2.9474155) 1537 4 lib8 lib9 lib8/lib9 lung: high met > low met 506 209 3.3833566 (15.730912) lib3 lib4 lib4/lib3 breast: low met > high met 987 2807 2.9149240 (30.381945) lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 26 8 2.4308253 (2.0970580) lib18 lib19 lib19/lib18 pt#3 colon: tumor > normal 6 26 3.7918237 (2.9890107) 1570 4 lib8 lib9 lib8/lib9 lung: high met > low met 506 209 3.3833566 (15.730912) lib3 lib4 lib4/lib3 breast: low met > high met 987 2807 2.9149240 (30.381945) lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 26 8 2.4308253 (2.0970580) lib18 lib19 lib19/lib18 pt#3 colon: tumor > normal 6 26 3.7918237 (2.9890107) 1590 4 lib8 lib9 lib8/lib9 lung: high met > low met 506 209 3.3833566 (15.730912) lib3 lib4 lib4/lib3 breast: low met > high met 987 2807 2.9149240 (30.381945) lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 26 8 2.4308253 (2.0970580) lib18 lib19 lib19/lib18 pt#3 colon: tumor > normal 6 26 3.7918237 (2.9890107) 2624 18 lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 80 13 4.6027462 (5.5144093) lib18 lib19 lib19/lib18 pt#3 colon: tumor > normal 10 80 7.0002899 (6.6596394) lib15 lib17 lib17/lib15 pt#3 colon: met > normal 4 23 5.3303793 (3.2702852) 2743 13 lib19 lib20 lib19/lib20 pt#3 colon: tumor > met 148 23 4.8128716 (7.6861840) lib18 lib20 lib20/lib18 pt#3 colon: met > normal 12 23 2.2423439 (2.1607719) lib18 lib19 lib19/lib18 pt#3 colon: tumor > normal 12 148 10.792113 (9.8617485) lib15 lib17 lib17/lib15 pt#2 colon: met > normal 14 80 5.2972714 (6.3458044) lib15 lib16 lib16/lib15 pt#2 colon: tumor > normal 14 50 3.4370927 (4.2243697) lib12 lib14 lib14/lib12 HMEC: VEGF > untreated 22 49 2.1811410 (2.9988774) 2759 1508 lib1 lib2 lib1/lib2 colon: high met > low met 46 17 2.5087292 (3.2300592) lib3 lib4 lib3/lib4 breast: high met > low met 21 5 4.0977674 (2.8791960) 2823 48 lib8 lib9 lib8/lib9 lung: high met > low met 342 155 3.0834574 (12.213852) lib3 lib4 lib4/lib3 breast: low met > high met 412 1020 2.5374934 (16.526285) 2851 1275 lib3 lib4 lib4/lib3 breast: low met > high met 15 32 2.1865564 (2.4185764) lib8 lib9 lib9/lib8 lung: low met > high met 10 42 3.0054239 3.1471113 high met = high metastatic potential; low met = low metastatic potential; met = metastasized; tumor = non-metastasized tumor; Pt = patient; #2 = UC#2; #3 = UC#3; HMEC = human microvascular endothelial cell; bFGF = bFGF treated; VEGF = VEGF treated

Example 12 Polynucleotides Exhibiting Colon-Specific Expression

The cDNA libraries described herein were also analyzed to identify those polynucleotides that were specifically expressed in colon cells or tissue, i.e., the polynucleotides were identified in libraries prepared from colon cell lines or tissue, but not in libraries of breast or lung origin. The polynucleotides that were expressed in a colon cell line and/or in colon tissue, but were present in the breast or lung cDNA libraries described herein, are shown in Table 35 (inserted before claims).

TABLE 35 Polynucleotides Specifically Expressed in Colon SEQ ID lib 1 lib 2 lib 15 lib 16 lib 17 lib 18 lib 19 lib 20 NO: Sequence Name cluster clones clones clones clones clones clones clones clones 847 RTA00000197AF.e.24.1 39250 2 0 0 0 0 0 0 0 851 RTA00000197AR.e.12.1 22095 3 0 0 0 0 0 0 0 860 RTA00000196AF.e.16.1 39252 2 0 0 0 0 0 0 0 862 RTA00000196AF.c.17.1 39602 2 0 0 0 0 0 0 0 865 RTA00000131A.g.19.2 36535 2 0 0 0 0 0 0 0 866 RTA00000187AR.o.10.2 8984 4 3 0 0 0 2 0 0 867 RTA00000198R.b.08.1 22636 3 0 0 0 0 0 0 0 870 RTA00000200R.g.09.1 22785 3 0 0 0 0 0 0 0 873 RTA00000200AF.b.19.1 22847 3 0 0 0 0 0 0 0 875 RTA00000200F.m.15.1 22601 3 0 0 0 1 0 0 0 881 RTA00000181AF.n.15.2 86128 1 0 0 0 0 0 0 0 882 RTA00000196R.k.07.1 22443 2 0 0 0 0 0 0 1 884 RTA00000200AR.e.02.1 36059 2 0 0 0 1 1 1 0 892 RTA00000177AR.a.23.5 6995 4 2 0 0 0 0 0 0 893 RTA00000198R.o.05.1 26702 2 0 0 0 0 0 0 0 894 RTA00000201R.a.02.1 35362 2 0 0 0 0 0 0 0 905 RTA00000197AF.h.11.1 22264 3 0 0 0 0 0 0 0 910 RTA00000199F.c.09.2 16824 3 1 0 0 0 0 0 0 919 RTA00000180AR.h.19.2 84182 1 0 0 0 0 0 0 0 922 RTA00000199R.f.09.1 22907 3 0 0 0 0 0 0 0 923 RTA00000199AF.p.4.1 10282 3 3 0 0 0 0 0 0 929 RTA00000200R.o.03.1 22807 3 0 0 0 0 0 0 0 930 RTA00000189AF.l.22.1 33333 1 1 0 0 0 0 0 0 931 RTA00000195AF.d.20.1 37574 2 0 0 0 0 0 0 0 936 RTA00000198AF.j.18.1 22759 3 0 0 0 0 0 0 0 939 RTA00000180AF.g.3.1 9024 5 2 0 0 0 0 0 0 946 RTA00000199R.j.08.1 37844 2 0 0 0 0 0 0 0 947 RTA00000199F.e.10.1 22906 3 0 0 0 0 0 1 0 949 RTA00000179AF.g.12.3 36390 2 0 0 0 0 0 0 0 952 RTA00000183AR.h.23.2 18957 3 0 0 0 0 0 0 0 953 RTA00000197AF.d.12.1 39546 2 0 0 0 0 0 0 0 960 RTA00000181AR.k.24.3 7005 8 2 0 0 0 0 0 0 963 RTA00000181AR.k.24.2 7005 8 2 0 0 0 0 0 0 968 RTA00000199AR.m.06.1 19122 3 0 0 0 0 0 0 0 973 RTA00000134A.d.10.1 18957 3 0 0 0 0 0 0 0 981 RTA00000181AF.m.4.3 13238 4 1 0 0 0 0 0 0 985 RTA00000196AF.c.6.1 23148 3 0 0 0 0 0 0 0 986 RTA00000198AF.k.19.1 75879 1 0 0 0 0 0 0 0 987 RTA00000199R.h.09.1 76020 1 0 0 0 0 0 0 0 988 RTA00000198AF.o.18.1 13018 4 0 0 0 1 0 0 0 992 RTA00000199F.h.17.2 36254 2 0 0 0 0 0 0 0 993 RTA00000181AR.h.06.3 87226 1 0 0 0 0 0 0 0 1010 RTA00000198AF.f.21.1 22676 3 0 0 0 0 0 0 0 1017 RTA00000200AR.b.07.1 17125 4 0 0 0 0 0 0 0 1022 RTA00000200F.o.03.1 22807 3 0 0 0 0 0 0 0 1024 RTA00000199AF.j.12.1 22461 3 0 0 0 0 0 0 0 1029 RTA00000195AF.d.4.1 22766 3 0 0 0 0 0 0 0 1038 RTA00000200R.k.01.1 40049 2 0 0 0 0 0 0 0 1039 RTA00000198AF.c.10.1 77149 1 0 0 0 0 0 0 0 1042 RTA00000197AR.e.07.1 86969 1 0 0 0 0 0 0 0 1043 RTA00000199R.c.09.1 16824 3 1 0 0 0 0 0 0 1050 RTA00000181AF.o.04.2 22205 3 0 0 0 0 0 0 0 1051 RTA00000199AF.l.19.1 22460 3 0 0 0 0 0 0 0 1052 RTA00000198AF.h.22.1 22366 2 1 0 0 0 0 0 0 1055 RTA00000199AF.m.15.1 10101 3 0 0 0 0 0 0 0 1056 RTA00000197AF.j.9.1 13236 4 1 0 0 0 0 0 0 1074 RTA00000185AR.b.18.1 12171 3 2 0 0 0 0 0 0 1079 RTA00000201AF.a.02.1 35362 2 0 0 0 0 0 0 0 1080 RTA00000183AR.h.23.1 18957 3 0 0 0 0 0 0 0 1082 RTA00000187AR.k.12.1 78415 1 0 0 0 0 0 0 0 1086 RTA00000198AF.m.17.1 77992 1 0 0 0 0 0 0 0 1087 RTA00000181AF.m.15.3 12081 4 0 0 0 0 0 0 0 1092 RTA00000198R.c.14.1 39814 2 0 0 0 0 0 0 0 1093 RTA00000200R.o.03.2 22807 3 0 0 0 0 0 0 0 1095 RTA00000192AF.n.13.1 8210 2 6 0 0 0 0 0 0 1100 RTA00000184AR.e.15.1 16347 4 0 0 0 0 0 0 0 1104 RTA00000198R.m.17.1 77992 1 0 0 0 0 0 0 0 1114 RTA00000178R.l.08.1 39648 2 0 0 0 0 0 0 0 1122 RTA00000198AF.p.16.1 71877 1 0 0 0 0 0 0 0 1124 RTA00000193AF.b.18.1 7542 8 0 0 2 1 0 1 0 1128 RTA00000199F.d.10.2 22049 3 0 0 0 0 0 0 0 1131 RTA00000200AF.b.07.1 17125 4 0 0 0 0 0 0 0 1132 RTA00000181AR.i.06.3 19119 3 0 0 0 0 0 0 0 1133 RTA00000196F.k.07.1 22443 2 0 0 0 0 0 0 1 1138 RTA00000198AF.k.23.1 8995 2 5 0 0 0 0 0 0 1140 RTA00000196AF.f.20.1 22774 3 0 0 0 0 0 0 0 1144 RTA00000195AF.c.12.1 37582 2 0 0 0 0 0 0 0 1146 RTA00000186AF.d.l.2 40044 2 0 0 1 0 0 0 0 1151 RTA00000200F.n.05.2 18989 3 0 0 0 0 0 0 0 1152 RTA00000178AF.j.20.1 15066 4 0 0 0 0 0 0 0 1154 RTA00000188AF.m.08.1 22155 3 0 0 0 0 0 0 0 1159 RTA00000199R.d.23.1 37477 2 0 0 0 0 0 0 0 1163 RTA00000200F.n.05.1 18989 3 0 0 0 0 0 0 0 1164 RTA00000196AF.m.13.1 16290 4 0 0 0 0 0 0 0 1169 RTA00000182AF.d.18.4 37435 2 0 0 0 0 0 0 0 1172 RTA00000200AF.g.09.1 22785 3 0 0 0 0 0 0 0 1174 RTA00000177AR.m.17.4 14391 3 1 0 0 0 0 0 0 1175 RTA00000197AR.c.20.1 16282 4 0 0 0 0 0 0 0 1181 RTA00000177AR.m.17.3 14391 3 1 0 0 0 0 0 0 1186 RTA00000196AF.d.10.1 22256 3 0 0 0 0 0 0 0 1187 RTA00000201F.a.18.1 16837 2 2 0 0 0 0 0 0 1188 RTA00000198AF.o.02.1 68756 1 0 0 0 0 0 0 0 1189 RTA00000187AF.h.21.1 39171 2 0 0 0 0 0 0 0 1191 RTA00000199F.b.03.2 38340 2 0 0 0 0 0 0 0 1202 RTA00000198AF.g.7.1 13386 3 2 0 0 0 0 0 0 1206 RTA00000197AR.c.24.1 82498 1 0 0 0 0 0 0 0 1215 RTA00000197F.e.7.1 86969 1 0 0 0 0 0 0 0 1222 RTA00000181AF.k.24.3 7005 8 2 0 0 0 0 0 0 1226 RTA00000200AF.j.6.1 22902 3 0 0 0 0 0 0 0 1228 RTA00000196AF.h.17.1 39215 2 0 0 0 0 0 0 0 1236 RTA00000185AF.b.11.2 9024 5 2 0 0 0 0 0 0 1241 RTA00000198AF.b.22.1 38956 2 0 0 0 0 0 0 0 1243 RTA00000186AF.m.15.2 40122 2 0 0 0 0 0 0 0 1250 RTA00000199F.f.09.2 22907 3 0 0 0 0 0 0 0 1252 RTA00000183AR.l.15.1 39383 2 0 0 0 0 0 0 0 1257 RTA00000200F.a.12.1 16751 4 0 0 0 0 0 0 0 1260 RTA00000199F.a.5.1 22134 3 0 0 0 0 0 0 0 1262 RTA00000187AR.k.01.1 78356 1 0 0 0 0 0 0 0 1268 RTA00000187AR.j.24.1 78356 1 0 0 0 0 0 0 0 1270 RTA00000199AF.o.19.1 36927 2 0 0 0 0 0 0 0 1273 RTA00000196F.i.19.1 39498 2 0 0 0 0 0 0 0 1274 RTA00000198R.k.23.1 8995 2 5 0 0 0 0 0 0 1276 RTA00000198AF.o.05.1 26702 2 0 0 0 0 0 0 0 1277 RTA00000198R.j.18.1 22759 3 0 0 0 0 0 0 0 1279 RTA00000182AR.c.22.1 16283 3 0 0 0 0 0 0 0 1282 RTA00000180AR.g.03.4 9024 5 2 0 0 0 0 0 0 1295 RTA00000200AF.b.20.1 40403 2 0 0 0 0 0 0 0 1299 RTA00000198AF.d.12.1 21142 2 1 0 0 0 0 0 0 1300 RTA00000200AF.b.12.1 22053 3 0 0 0 0 0 0 0 1301 RTA00000191AR.l.7.2 14391 3 1 0 0 0 0 0 0 1305 RTA00000190AF.e.13.1 38961 2 0 0 0 0 0 0 0 1306 RTA00000196AF.n.17.1 12477 4 1 0 0 0 0 0 0 1311 RTA00000195AF.b.19.1 77678 1 0 0 0 0 0 0 0 1319 RTA00000187AR.m.3.3 17055 4 0 0 0 0 0 0 0 1320 RTA00000200R.g.15.1 22898 3 0 0 0 0 0 0 0 1326 RTA00000187AF.j.7.1 78091 1 0 0 0 0 0 0 0 1329 RTA00000196AF.c.14.1 23105 3 0 0 0 0 0 0 0 1330 RTA00000190AR.p.22.2 16368 4 0 0 0 0 0 0 0 1336 RTA00000198AF.b.8.1 22636 3 0 0 0 0 0 0 0 1337 RTA00000177AF.m.17.1 14391 3 1 0 0 0 0 0 0 1338 RTA00000200AF.k.1.1 40049 2 0 0 0 0 0 0 0 1342 RTA00000190AF.h.12.1 12977 5 0 0 0 0 0 0 0 1343 RTA00000199F.b.22.2 17018 4 0 0 0 0 0 0 0 1352 RTA00000187AF.i.14.2 19406 2 1 0 0 0 0 0 0 1355 RTA00000196AF.g.10.1 12498 3 1 1 0 0 0 0 0 1361 RTA00000184AF.e.14.1 16347 4 0 0 0 0 0 0 0 1366 RTA00000178AR.h.17.2 23824 2 1 0 0 0 0 0 0 1375 RTA00000195F.a.3.1 27179 2 0 0 0 0 0 0 0 1388 RTA00000196F.j.13.1 23170 3 0 0 0 0 0 0 0 1391 RTA00000196AF.g.8.1 39665 2 0 0 0 0 0 0 0 1393 RTA00000198AF.c.16.1 26801 2 0 0 0 0 0 0 0 1397 RTA00000201F.b.22.1 35728 2 0 0 0 0 0 0 1 1403 RTA00000197AF.p.20.1 22795 3 0 0 0 0 0 0 0 1407 RTA00000192AR.o.16.2 9061 5 2 0 0 0 0 0 0 1409 RTA00000191AF.c.10.1 40422 2 0 0 0 0 0 0 0 1412 RTA00000196AF.p.01.2 87143 1 0 0 0 0 0 0 0 1422 RTA00000180AF.g.17.1 16653 3 1 0 0 0 0 0 0 1427 RTA00000190AR.h.12.2 12977 5 0 0 0 0 0 0 0 1429 RTA00000198AF.n.18.1 16715 3 1 0 0 0 0 0 0 1430 RTA00000199R.o.11.1 23172 3 0 0 0 0 0 0 0 1432 RTA00000191AF.b.4.1 14936 3 0 0 0 0 0 0 0 1433 RTA00000192AF.l.1.1 16392 3 0 0 0 0 0 0 0 1437 RTA00000196R.c.14.2 23105 3 0 0 0 0 0 0 0 1439 RTA00000195R.a.06.1 35265 2 0 1 0 0 0 0 0 1446 RTA00000195AF.b.21.1 39055 2 0 0 0 0 0 0 0 1456 RTA00000197AR.e.22.1 78758 1 0 0 0 0 0 0 0 1459 RTA00000197R.p.20.1 22795 3 0 0 0 0 0 0 0 1462 RTA00000192AF.a.14.1 6874 6 3 0 0 1 0 0 0 1467 RTA00000198R.b.24.1 19047 3 0 0 0 0 0 0 0 1471 RTA00000199F.h.15.2 22269 3 0 0 0 0 0 0 0 1472 RTA00000198AF.g.16.1 6602 1 1 0 0 0 0 0 0 1478 RTA00000192AF.j.6.1 11494 4 0 0 0 0 0 0 0 1479 RTA00000181AF.p.7.3 38773 2 0 0 0 0 0 0 0 1481 RTA00000200AF.g.15.1 22898 3 0 0 0 0 0 0 0 1487 RTA00000184AF.c.9.1 16245 4 0 0 0 0 0 0 0 1489 RTA00000177AF.k.9.1 16245 4 0 0 0 0 0 0 0 1493 RTA00000190AR.l.19.2 88204 1 0 0 0 0 0 0 0 1506 RTA00000201R.a.15.1 57347 1 0 0 0 0 0 0 0 1508 RTA00000195R.a.23.1 86432 1 0 0 0 0 0 0 0 1514 RTA00000186AF.p.17.3 38383 2 0 0 0 0 0 0 0 1518 RTA00000197AR.e.24.1 39250 2 0 0 0 0 0 0 0 1527 RTA00000187AR.j.01.1 79028 1 0 0 0 0 0 0 0 1530 RTA00000201F.f.07.1 51116 1 0 0 0 0 0 0 0 1538 RTA00000201R.c.19.1 22357 2 1 0 0 0 0 0 0 1546 RTA00000177AR.b.8.5 17062 3 0 0 0 0 0 0 0 1556 RTA00000201F.b.21.1 9071 3 4 0 0 0 0 0 0 1561 RTA00000200F.o.10.2 36432 2 0 0 0 0 0 0 0 1562 RTA00000196F.l.14.2 23144 3 0 0 0 0 0 0 0 1569 RTA00000197AF.b.1.1 12134 1 1 0 0 0 0 0 0 1577 RTA00000200AF.d.20.1 26600 2 0 0 0 0 0 0 0 1587 RTA00000178AF.k.9.1 16342 3 0 0 0 0 0 0 0 1592 RTA00000198AF.b.24.1 19047 3 0 0 0 0 0 0 0 1601 RTA00000406F.d.16.1 15040 2 2 0 0 0 0 0 0 1604 RTA00000408F.o.12.2 78578 1 0 0 0 0 0 0 0 1605 RTA00000119A.j.15.1 79623 1 0 0 0 0 0 0 0 1606 RTA00000413F.d.12.1 66467 1 0 0 0 0 0 0 0 1607 RTA00000423F.i.12.1 9118 4 3 0 0 0 0 0 0 1610 RTA00000411F.k.05.1 64777 1 0 0 0 0 0 0 0 1613 RTA00000419F.b.09.1 78128 1 0 0 0 0 0 0 0 1616 RTA00000411F.m.15.1 78014 1 0 0 0 0 0 0 0 1618 RTA00000123A.k.23.1 80313 1 0 0 0 0 0 0 0 1621 RTA00000130A.m.15.1 81630 1 0 0 0 0 0 0 0 1622 RTA00000411F.k.20.1 64973 1 0 0 0 0 0 0 0 1624 RTA00000418F.k.05.1 73021 1 0 0 0 0 0 0 0 1625 RTA00000423F.h.18.1 37972 2 0 0 0 0 0 0 0 1627 RTA00000422F.p.06.2 39282 2 0 0 0 0 0 0 0 1628 RTA00000404F.n.16.2 39095 2 0 0 0 0 0 0 0 1629 RTA00000411F.m.24.1 77568 1 0 0 0 0 0 0 0 1630 RTA00000134A.j.10.1 81383 1 0 0 0 0 0 0 0 1631 RTA00000409F.j.02.1 76417 1 0 0 0 0 0 0 0 1632 RTA00000403F.j.15.1 23840 2 1 0 0 0 0 0 0 1633 RTA00000411F.n.11.1 77276 1 0 0 0 0 0 0 0 1634 RTA00000339F.i.13.1 5970 6 4 0 0 0 0 0 0 1636 RTA00000406F.o.15.1 37482 2 0 0 0 0 0 0 0 1637 RTA00000412F.g.04.2 64457 1 0 0 0 0 0 0 0 1639 RTA00000352R.l.06.1 40343 2 0 0 0 0 0 0 0 1640 RTA00000419F.b.12.1 63148 1 0 0 0 0 0 0 0 1641 RTA00000423F.k.17.2 37512 2 0 0 0 0 0 0 0 1643 RTA00000418F.k.14.1 76133 1 0 0 0 0 1 0 0 1644 RTA00000409F.l.12.1 26755 1 0 0 0 0 0 0 0 1645 RTA00000404F.c.20.1 39088 2 0 0 0 0 0 1 0 1646 RTA00000423F.g.09.1 38958 2 0 0 0 0 0 0 0 1648 RTA00000406F.d.12.1 38575 2 0 0 0 0 0 0 0 1649 RTA00000411F.f.02.1 63386 1 0 0 0 0 0 0 0 1650 RTA00000129A.n.21.1 79381 1 0 0 0 0 0 0 0 1651 RTA00000409F.m.12.1 73490 1 0 0 0 0 0 0 0 1652 RTA00000410F.c.04.1 74099 1 0 0 0 0 0 0 0 1654 RTA00000406F.m.09.1 26891 2 0 0 0 0 0 0 0 1655 RTA00000411F.b.06.1 77884 1 0 0 0 0 0 0 0 1656 RTA00000409F.l.21.1 73143 1 0 0 0 0 0 0 0 1662 RTA00000404F.l.20.2 38638 2 0 0 0 0 0 0 0 1663 RTA00000413F.d.18.1 65305 1 0 0 0 0 0 0 0 1664 RTA00000404F.p.04.2 39069 2 0 0 0 0 0 0 0 1665 RTA00000405F.g.19.2 37150 2 0 0 0 0 0 0 0 1666 RTA00000409F.a.22.1 75200 1 0 0 0 0 0 0 0 1668 RTA00000405F.o.18.1 11016 4 2 0 0 0 0 0 0 1673 RTA00000408F.e.22.2 26930 1 0 0 0 0 0 0 0 1675 RTA00000413F.d.16.1 63331 1 0 0 0 0 0 0 0 1678 RTA00000419F.g.08.1 66700 1 0 0 0 0 0 0 0 1679 RTA00000122A.g.16.1 81366 1 0 0 0 0 0 0 0 1680 RTA00000419F.c.16.1 65254 1 0 0 0 0 0 0 0 1681 RTA00000411F.b.03.1 23634 1 2 0 0 0 0 0 0 1686 RTA00000403F.l.20.1 18267 1 0 0 0 0 0 0 0 1689 RTA00000411F.a.02.1 78537 1 0 0 0 0 0 0 0 1691 RTA00000412F.l.04.1 66372 1 0 0 0 0 0 0 0 1693 RTA00000406F.a.23.1 38712 2 0 0 0 0 0 0 0 1695 RTA00000120A.n.19.3 80004 1 0 0 0 0 0 0 0 1696 RTA00000403F.e.01.1 38965 2 0 0 0 0 0 0 0 1697 RTA00000411F.l.03.1 62702 1 0 0 0 0 0 0 0 1700 RTA00000121A.m.2.1 81064 1 0 0 0 0 0 0 0 1702 RTA00000418F.j.12.1 73316 1 0 0 0 0 0 0 0 1706 RTA00000125A.g.16.1 21497 2 1 0 0 0 0 0 0 1707 RTA00000418F.o.18.1 78676 1 0 0 0 0 0 0 0 1709 RTA00000408F.k.14.1 73856 1 0 0 0 0 0 0 0 1715 RTA00000403F.o.15.1 39140 2 0 0 0 0 0 0 0 1716 RTA00000341F.m.13.1 26502 1 0 0 0 0 0 0 0 1717 RTA00000408F.h.03.1 78382 1 0 0 0 0 0 0 0 1718 RTA00000423F.k.05.1 37472 2 0 0 0 0 0 0 0 1720 RTA00000418F.p.19.1 78544 1 0 0 0 0 0 0 0 1721 RTA00000420F.f.06.1 64812 1 0 0 0 0 0 0 0 1722 RTA00000122A.j.18.1 81317 1 0 0 0 0 0 0 0 1723 RTA00000420F.d.05.1 64432 1 0 0 0 0 0 0 0 1724 RTA00000403F.m.18.1 39185 2 0 0 0 0 0 0 0 1726 RTA00000411F.j.05.1 40709 1 1 0 0 0 0 0 0 1727 RTA00000403F.a.04.1 23529 2 1 0 0 0 0 0 0 1729 RTA00000406F.f.12.1 21895 2 1 0 0 0 0 0 0 1730 RTA00000418F.g.22.1 74837 1 0 0 0 0 0 0 0 1732 RTA00000404F.l.20.1 38638 2 0 0 0 0 0 0 0 1733 RTA00000408F.i.08.2 75811 1 0 0 0 0 0 0 0 1734 RTA00000122A.d.5.1 81155 1 0 0 0 0 0 0 0 1738 RTA00000419F.b.19.1 65534 1 0 0 0 0 0 0 0 1740 RTA00000418F.k.19.1 74932 1 0 0 0 0 0 0 0 1744 RTA00000419F.g.12.1 66171 1 0 0 0 0 0 0 0 1745 RTA00000404F.n.11.2 38001 2 0 0 0 0 0 0 0 1748 RTA00000419F.o.24.1 65092 1 0 0 0 0 0 0 0 1749 RTA00000419F.k.19.1 75447 1 0 0 0 0 0 0 0 1751 RTA00000127A.i.20.1 81418 1 0 0 0 0 0 0 0 1752 RTA00000422F.g.22.1 22561 3 0 0 0 0 0 0 0 1754 RTA00000413F.h.13.1 65190 1 0 0 0 0 0 0 0 1757 RTA00000348R.j.16.1 7005 8 2 0 0 0 0 0 0 1760 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RTA00000527F.j.12.2 37503 2 0 0 0 0 0 0 0 3243 RTA00000522F.g.11.1 75432 1 0 0 0 0 0 0 0 3244 RTA00000522F.k.02.2 77622 1 0 0 0 0 0 0 0 3245 RTA00000427F.e.13.1 66080 1 0 0 0 0 0 0 0 3246 RTA00000426F.f.18.1 63271 1 0 0 0 0 0 0 0 3247 RTA00000427F.a.12.1 63377 1 0 0 0 0 0 0 0 3248 RTA00000424F.b.23.4 77322 1 0 0 0 0 0 0 0 3252 RTA00000427F.f.02.1 36822 2 0 0 0 0 0 0 0 3254 RTA00000424F.i.15.1 78043 1 0 0 0 0 0 0 0 3256 RTA00000522F.m.03.1 79194 1 0 0 0 0 0 0 0 3257 RTA00000522F.a.20.1 74070 1 0 0 0 0 0 0 0 3258 RTA00000424F.b.15.4 74958 1 0 0 0 0 0 0 0 3259 RTA00000527F.g.14.1 37532 2 0 0 0 0 0 0 0 3260 RTA00000522F.d.06.1 74809 1 0 0 0 0 0 0 0 3262 RTA00000427F.e.10.1 64599 1 0 0 0 0 0 0 0 3263 RTA00000527F.c.16.1 22908 3 0 0 0 0 0 0 0 3265 RTA00000523F.f.17.1 63984 1 0 0 0 0 0 0 0 3267 RTA00000527F.p.24.1 36832 2 0 0 0 0 0 0 0 3268 RTA00000425F.n.17.1 78304 1 0 0 0 0 0 0 0 3270 RTA00000425F.e.07.1 75992 1 0 0 0 0 0 0 0 3272 RTA00000523F.h.08.1 62893 1 0 0 0 0 0 0 0 3273 RTA00000522F.o.10.1 78798 1 0 0 0 0 0 0 0 3274 RTA00000425F.l.10.1 26893 1 0 0 0 0 0 0 0 3275 RTA00000427F.f.16.1 64122 1 0 0 0 0 0 0 0 3278 RTA00000425F.i.10.1 78736 1 0 0 0 0 0 0 0 3279 RTA00000426F.m.12.1 63740 1 0 0 0 0 0 0 0 3280 RTA00000527F.g.12.1 37746 2 0 0 0 0 0 0 0 3283 RTA00000425F.i.18.1 42255 1 1 0 0 0 0 0 0 3285 RTA00000424F.j.13.1 74485 1 0 0 0 0 0 0 0 3289 RTA00000424F.k.10.1 73232 1 0 0 0 0 0 0 0 3290 RTA00000522F.i.07.2 78377 1 0 0 0 0 0 0 0 3292 RTA00000522F.b.08.1 26915 1 0 0 0 0 0 0 0 3293 RTA00000522F.l.08.1 78781 1 0 0 0 0 0 0 0 3294 RTA00000525F.a.14.1 37566 2 0 0 0 0 0 0 0 3295 RTA00000424F.g.08.1 74928 1 0 0 0 0 0 0 0 3296 RTA00000425F.l.09.1 75251 1 0 0 0 0 0 0 0 3297 RTA00000522F.o.20.1 74853 1 0 0 0 0 0 0 0 3298 RTA00000527F.j.04.2 11809 3 1 0 0 0 0 0 0 3300 RTA00000523F.c.13.1 40668 1 1 0 0 0 0 0 0 3301 RTA00000427F.i.21.1 65540 1 0 0 0 0 0 0 0 3303 RTA00000522F.h.02.1 74947 1 0 0 0 0 0 0 0 3304 RTA00000522F.g.10.1 74294 1 0 0 0 0 0 0 0 3308 RTA00000425F.k.16.1 75282 1 0 0 0 0 0 0 0 3309 RTA00000525F.b.09.1 23472 2 1 0 0 0 0 0 0 3310 RTA00000522F.j.08.2 76613 1 0 0 0 0 0 0 0 3312 RTA00000523F.f.19.1 34169 1 1 0 0 0 0 0 0 3313 RTA00000425F.j.18.1 75561 1 0 0 0 0 1 0 0 3314 RTA00000426F.m.04.1 36865 2 0 0 0 0 0 0 0 3315 RTA00000527F.g.21.1 36028 2 0 0 0 0 0 0 0 3317 RTA00000525F.a.22.1 36848 2 0 0 0 0 0 0 0 3318 RTA00000522F.p.22.1 73322 1 0 0 0 0 0 0 0 3319 RTA00000424F.d.12.2 74342 1 0 0 0 0 0 0 0 3320 RTA00000424F.g.24.1 79156 1 0 0 0 0 0 0 0 3321 RTA00000427F.a.10.1 65370 1 0 0 0 0 0 0 0 3322 RTA00000426F.h.20.1 23187 3 0 0 0 0 0 0 0 3323 RTA00000424F.d.12.3 74342 1 0 0 0 0 0 0 0 3324 RTA00000425F.c.03.1 74643 1 0 0 0 0 0 0 0 3325 RTA00000523F.f.16.1 26522 1 0 0 0 0 0 0 0 3326 RTA00000427F.f.15.1 66734 1 0 0 0 0 0 0 0 3329 RTA00000522F.p.18.1 76376 1 0 0 0 0 0 0 0 3337 RTA00000522F.g.18.1 73226 1 0 0 0 0 0 0 0 3339 RTA00000522F.h.05.1 73358 1 0 0 0 0 0 0 0 3341 RTA00000425F.n.16.1 18265 1 0 0 0 0 0 0 0 3342 RTA00000527F.l.21.1 36439 2 0 0 0 0 0 0 0 3345 RTA00000424F.d.17.3 73958 1 0 0 0 0 0 0 0 3346 RTA00000523F.j.02.1 62853 1 0 0 0 0 0 0 0

No clones corresponding to the colon-specific polynucleotides in the table above resent in any of Libraries 3, 4, 8, 9, 12, 13, 14, or 15. The polynucleotide provided above can be used as markers of cells of colon origin, and find particular use in reference arrays, as described above.

Example 26 Identification of Contiguous Sequences Having a Polynucleotide of the Invention

The novel polynucleotides were used to screen publicly available and proprietary databases to determine if any of the polynucleotides of SEQ ID NOS: 845-3346 would facilitate identification of a contiguous sequence, e.g., the polynucleotides would provide sequence that would result in 5′ extension of another DNA sequence, resulting in production of a longer contiguous sequence composed of the provided polynucleotide and the other DNA sequence(s). Contiging was performed using the Gelmerge application (default settings) of GCG from the Univ. of Wisconsin.

Using these parameters, 146 contiged sequences were generated. These contiged sequences are provided as SEQ ID NOS:5951-6096 (see Table 17). The contiged sequences can be correlated with the sequences of SEQ ID NOS:845-3346 upon which the contiged sequences are based by, for example, identifying those sequences of SEQ ID NOS: 845-3346 and the contiged sequences of SEQ ID NOS: 5951-6096 that share the same clone name in Table 17.

The contiged sequences (SEQ ID NO: 5951-6096) thus represent longer sequences that encompass a polynucleotide sequence of the invention. The contiged sequences were then translated in all three reading frames to determine the best alignment with individual sequences using the BLAST programs as described above for SEQ ID NOS: 845-3346 and the validation sequences “SEQ ID NOS:3347-5950.” Again the sequences were masked using the XBLAST program for masking low complexity as described above in Example 1 (Table 18). Several of the contiged sequences were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 36). Thus the invention encompasses fragments, fusions, and variants of such polynucleotides that retain biological activity associated with the protein family and/or functional domain identified herein.

TABLE 36 Profile hits using contiged sequences SEQ Biological Activity ID NO (Profile) Start Stop Score Direction Sequence Name 5955 7tm_2 71 915 8090 for RTA00000399F.o.01.1 5964 7tm_2 101 919 8475 rev RTA00000341F.m.21.1 6018 7tm_2 3 963 9431 for RTA00000192AF.h.19.1 6041 7tm_2 214 1073 8528 rev RTA00000192AF.f.3.1 6052 ANK 546 629 4920 for RTA00000190AF.f.5.1 5964 asp 126 1067 6620 rev RTA00000341F.m.21.1. 6085 asp 112 1094 6553 for RTA00000418F.i.06.1 6087 asp 347 1028 5981 for RTA00000339F.b.02.1 6041 ATPases 113 781 5690 for RTA00000192AF.f.3.1 6083 ATPases 1 348 15955 for RTA00000401F.m.07.1 6085 ATPases 110 823 6782 for RTA00000418F.i.06.1 6087 ATPases 338 874 5832 for RTA00000339F.b.02.1 5969 protkinase 59 685 5791 for RTA00000182AF.c.5.1 6061 protkinase 75 1035 5405 for RTA00000181AF.p.12.3 6081 protkinase 25 546 5107 rev RTA00000118A.n.5.1 6092 protkinase 14 422 5103 rev RTA00000419F.k.05.1 6096 protkinase 89 755 5499 for RTA00000404F.m.17.2 5964 Wnt_dev_sign 3 948 11036 for RTA00000341F.m.21.1 All stop/start sequences are provided in the forward direction.

Descriptions of the profiles for the indicated protein families and functional domains are provided in Example 3 above.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Deposit Information:

The following materials were deposited with the American Type Culture Collection: CMCC=(Chiron Master Culture Collection)

Cell Lines Deposited with ATCC ATCC CMCC Cell Line Deposit Date Accession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377 cDNA Libraries Deposited with ATCC cDNA Library No. cDNA Library ES21 cDNA Library ES22 cDNA Library ES23 Deposit Date Jan. 22, 1999 Jan. 22, 1999 Jan. 22, 1999 ATCC Accession No. ATCC No. ATCC No. ATCC No. Clone M00001575D:G05 M00001364A:E11 M00001489B:A06 Names M00001460A:A03 M00001694C:H10 M00001585A:D06 M00001655C:E04 M00003841D:E03 M00001637B:E07 M00001676C:C11 M00004176D:B12 M00001529D:H02 M00001679D:D05 M00001387B:E02 M00001500C:C08 M00001546B:C05 M00004282B:A04 M00001483B:D03 M00001453B:E10 M00001376B:F03 M00001623C:H07 M00001445D:A06 M00003975B:F03 M00001399C:H12 M00004208D:H08 cDNA Library No. cDNA Library ES24 cDNA Library ES25 cDNA Library ES26 Deposit Date Jan. 22, 1999 Jan. 22, 1999 Jan. 22, 1999 ATCC Accession No. ATCC No. ATCC No. ATCC No. Clone M00003987D:D06 M00001675D:B08 M00001479C:F10 Names M00004073A:H12 M00001589B:E12 M00003842D:F08 M00004104B:F11 M00001607D:A11 M00003901A:C09 M00004237D:D08 M00001636A:E07 M00003982A:B06 M00004111D:B07 M00001530A:B12 M00003824A:A06 M00004138B:B11 M00001495B:B08 M00003845D:C03 M00001391C:C04 M00001487C:F01 M00003856A:B07 M00001448D:E12 M00001644B:D06 M00004104B:A02 M00001450A:B03 M00003751C:A04 M00004110C:E03 M00001451B:F01

In addition, libraries of selected clones were deposited. The details of these deposits are provided in Tables 37-40.

This deposit is provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

TABLE 37 Clones Deposited on Jan. 22, 1999 cDNA LIbrary Ref. Library ES17 Library ES18 Library ES19 ATCC No 207064 207065 207066 Clone M00001601A:E09 M00001594A:D06 M00003906A:F04 Names M00001368A:D07 M00001613D:H10 M00003908A:F12 M00003917A:D02 M00001596D:E10 M00003914A:G09 M00001673A:A04 M00001592C:G04 M00003915C:H04 M00003868B:G11 M00001599D:A09 M00003905D:B08 M00003917C:D03 M00001619B:A09 M00003908C:G09 M00003791C:E09 M00001593B:E11 M00003914B:A11 M00003870A:C05 M00001605A:E06 M00003916C:C05 M00003922A:D02 M00001608A:D03 M00003959A:A03 M00003861C:H02 M00001616C:A02 M00003905D:C08 M00003931B:A11 M00001617A:D06 M00003908D:D12 M00001679D:B05 M00001595C:E01 M00003901B:H04 M00001679C:D05 M00001616C:A11 M00004031A:E01 M00001687A:G01 M00001608C:E11 M00004029C:C12 M00003945A:E09 M00001610C:E06 M00003911A:F10 M00003908A:H09 M00001612B:D11 M00003914C:F09 M00001649B:G12 M00001618B:E05 M00003963D:B05 M00003813D:H12 M00001621C:C10 M00003986C:E09 M00004087C:D03 M00001647A:H08 M00004031A:F07 M00004269B:C08 M00001631D:B10 M00003907C:C02 M00004348A:A02 M00001608D:E09 M00003911B:F08 M00001679C:D01 M00001641B:C10 M00003914C:H05 M00001490A:E11 M00001641D:E02 M00003918C:C12 M00001387A:E10 M00001630D:H10 M00003914C:C02 M00001397B:G03 M00001585C:D10 M00003914A:E04 M00001441D:E04 M00001560A:H10 M00003903B:D03 M00001352C:G09 M00001573B:C06 M00003905A:F09 M00001370D:A12 M00001660C:D11 M00003867C:E11 M00001387B:A06 M00001641C:C05 M00003870B:B08 M00001397C:A10 M00001578B:B05 M00003879D:A08 M00001536D:G02 M00001587C:C10 M00003891D:B10 M00003895C:A10 M00001590B:C07 M00003901C:A08 M00001464B:B03 M00001554A:E04 M00003903C:C04 M00004370A:G05 M00001570C:G06 M00003905A:F10 M00001490B:H11 M00001576A:B09 M00003906C:D06 M00001530B:D10 M00001582A:H01 M00003907D:A12 M00001579C:E09 M00001582B:E12 M00003905C:G11 M00001587A:H03 M00001615B:F07 M00003914D:D10 M00001457C:H12 M00001571C:A04 M00003972A:G09 M00001535C:E01 M00001573D:D10 M00003975D:C06 M00001561D:C05 M00001576A:F11 M00003905C:B02 M00001589A:C01 M00001579C:G05 M00003907D:F11 M00001664D:G07 M00001582D:A02 M00003914A:G06 M00001565A:H09 M00001589B:E07 M00003914D:E03 M00001381C:B08 M00001575B:B02 M00003972C:F08 M00001395C:F11 M00001578C:G06 M00003976C:D06 M00001429D:F11 M00001591A:B08 M00003907C:C04 M00001449A:F01 M00001607A:F11 M00003905B:C06 M00001391C:H02 M00001579C:E06 M00004088C:A12 M00001429D:H12 M00001661C:F11 M00004103C:D04 M00001450A:G11 M00001650B:C10 M00004107A:D01 M00001344B:F12 M00001654C:E04 M00004110A:E04 M00001391D:C06 M00001656B:A08 M00004062A:H06 M00003971A:A06 M00001662C:B02 M00004075D:C10 M00001346A:E04 M00001656B:D05 M00004081D:H09 M00001455C:G07 M00001661C:F10 M00004089A:B08 M00001402D:F02 M00001663A:C11 M00004103D:F10 M00001438D:C06 M00001669A:C10 M00004107B:B04 M00001349B:G05 M00001651B:B12 M00004032C:B02 M00001389C:A08 M00001653B:E06 M00004078C:F04 M00001439B:A10 M00001659C:F02 M00004038B:H10 M00001455B:A09 M00001661B:F03 M00004089A:E02 M00001441B:D11 M00001663C:F10 M00004096B:F05 M00001453A:B01 M00001669A:G12 M00004104C:H12 M00001456D:E08 M00001674D:C10 M00004110D:A10 M00001399A:C03 M00001651B:E06 M00004036D:F02 M00004496C:H03 M00001651C:C05 M00004088C:E04 M00004135D:G02 M00001657C:C07 M00004104D:A04 M00004692A:E07 M00001662A:C12 M00004107D:E12 M00004374D:E10 M00001663D:C06 M00004115D:D08 M00004405D:C04 M00001590B:C05 M00003846A:D03 M00004312B:H07 M00001483C:G06 M00004072C:F08 M00003976C:A10 M00001653A:G07 M00004039B:G08 M00004043A:D02 M00001625B:C10 M00003986D:D02 M00004081C:H06 M00001626C:D12 M00003914A:B07 M00004050D:A06 M00001634D:D02 M00003914D:B02 M00001361B:C07 M00001641C:C06 M00003971B:B07 M00004341B:G03 M00001642D:F02 M00003978C:A03 M00001342B:E01 M00001647B:E04 M00003983B:C08 M00004064D:A11 M00001632B:E05 M00004033D:D07 M00004087A:G08 M00001639A:C11 M00004072D:H12 M00004344B:H04 M00001642D:G10 M00004077B:H11 M00004497A:H03 M00001624A:G11 M00004080A:F01 M00001338C:E10 M00001626C:G08 M00004092C:B03 M00001366D:E12 M00001672D:D04 M00004037B:C04 M00001390D:E03 M00001639A:H06 M00004073C:D04 M00001413B:H09 M00001662C:A04 M00004081A:A08 M00004271B:B06 M00001641B:B01 M00004085B:B05 M00004151D:E03 M00001673C:A02 M00004090C:C07 M00001660B:C04 M00001650A:A12 M00004086D:B09 M00003802D:B11 M00001659D:D03 M00004088D:B03 M00001579C:E08 M00001661B:B05 M00004090C:C10 M00001557D:C08 M00001671D:E10 M00004102C:D09 M00003779B:E12 M00001652D:A06 M00004105C:E09 M00001638A:D10 M00001654C:D05 M00004035A:G10 M00003794A:B03 M00001656A:B07 M00003906A:H07 M00001616C:F07 M00001647B:C09 M00004083B:G03 M00001679A:F01 M00001635A:C06 M00001675B:E02 M00001604C:E09 M00001482D:A04 M00003793C:D09 M00001653B:E09 M00001485C:B10 M00003762B:H09 M00001585A:F07 M00001457D:A07 M00001694C:F12 M00003811D:A12 M00001461A:E05 M00001678D:C11 M00001653C:F12 M00001477A:G07 M00001677D:B07 M00001679D:F06 M00001479D:H03 M00001677B:A02 M00003751D:B02 M00001482C:D02 M00001675B:H03 M00003801A:B10 M00001484D:G05 M00003808D:D04 M00003844C:A08 M00001459B:D03 M00003752B:C02 M00001636C:C01 M00001464B:C11 M00003819D:B11 M00001669C:B01 M00001511A:A05 M00001677D:B02 M00003755A:A09 M00001477B:C02 M00001694C:G04 M00003798D:H08 M00001471A:D04 M00003789C:F06 M00001444C:D05 M00001485C:H10 M00001678C:C06 M00004040B:F10 M00001485D:E05 M00001675B:D02 M00001355A:C12 M00001487C:G03 M00003750C:H05 M00001401A:H07 M00001514A:B04 M00001694A:B12 M00001393B:B09 M00001530C:G10 M00001677B:H06 M00001409D:F11 M00001534A:G06 M00001675C:G01 M00001387B:H07 M00001539A:C12 M00001675B:C01 M00001394C:C11 M00001547A:F11 M00003857B:F07 M00001344A:H07 M00001550D:A04 M00003812B:D07 M00001490C:D07 M00001460A:F07 M00001694B:B08 M00001352C:F06 M00001472C:A01 M00001677B:E06 M00001476D:G03 M00001481B:A07 M00004037A:E04 M00001399C:D09 M00001456D:F05 M00003870A:H01 M00001347C:G08 M00001456D:G11 M00003842C:D11 M00001453D:G12 M00001477D:F10 M00003828B:F09 M00001382A:F04 M00001481A:G06 M00003856C:H09 M00001392D:H04 M00001464A:B03 M00003851A:C10 M00001429C:G12 M00001469A:G11 M00003841C:E04 M00001454A:C11 M00001478B:D07 M00003837C:G08 M00001517B:G08 M00001473A:C11 M00003828B:E07 M00001535A:D02 M00001457A:G03 M00003772C:B12 M00001352A:E12 M00001669B:G02 M00001677D:F03 M00001381B:F06 M00001479D:G06 M00001678B:B12 M00004117A:D11 M00001473D:B11 M00001678D:G03 M00004217C:D03 M00001475A:A12 M00001675C:F01 M00004270A:F11 M00001460A:G07 M00003809A:H04 M00003996A:A06 M00001464A:D03 M00003771D:G05 M00004056B:D09 M00001473D:G01 M00001678A:F05 M00004142A:B12 M00001476D:C05 M00001677B:B06 M00001396D:B03 M00001484A:A10 M00003794A:E12 M00001370D:E12 M00001457C:F02 M00003771B:E05 M00001390C:C11 M00001459B:A12 M00001678A:A11 M00003989A:H11 M00001464A:E07 M00003805B:C04 M00001426A:A09 M00001467A:B03 M00001680B:E10 M00004498D:D05 M00001514A:B08 M00001679B:H07 M00001391B:G12 M00001464A:B07 M00003904D:B12 M00001391D:D10 M00001579A:C03 M00003856C:B08 M00001376B:A02 M00001517A:G08 M00003858D:G06 M00001405B:D07 M00001530B:G09 M00003870B:F04 M00001368A:A03 M00001538A:F12 M00003871C:B05 M00001392D:B11 M00001540C:B03 M00003875A:C04 M00003900D:B10 M00001547A:F06 M00003901B:A09 M00001494B:C01 M00001550A:F07 M00003901C:D03 M00001352C:A05 M00001567B:G11 M00003904C:B06 M00001408B:G06 M00001572A:A10 M00003901C:F09 M00004252C:E03 M00001575B:G01 M00003904D:B10 M00003901C:A03 M00001487D:C11 M00003850D:H11 M00004071D:A10 M00001577B:A03 M00003902B:D06 M00001377B:H01 M00001539D:E10 M00003879A:C01 M00003939A:A02 M00001587A:F05 M00003877D:G05 M00004250D:D10 M00001560A:F03 M00003881D:C12 M00004290A:B03 M00001569B:G11 M00003903A:H09 M00003911D:B04 M00001573A:A06 M00003905A:A06 M00004128B:G01 M00001575D:A10 M00003875D:D09 M00004142A:D08 M00001583A:D01 M00003879B:A06 M00003977A:E04 M00001587A:F08 M00003823D:G05 M00004236C:D10 M00001590B:B02 M00003763A:C01 M00004388B:A08 M00001553A:E07 M00003903B:C02 M00004409B:A11 M00001560A:H06 M00003905A:E07 M00003965A:B11 M00001589C:A11 M00003867A:D12 M00003988A:E10 M00001538A:C08 M00003857C:C09 M00004138A:H09 M00001531A:H03 M00003829C:D10 M00003933C:D06 M00001548A:G01 M00003839D:E02 M00004193C:G11 M00001531A:H07 M00003841C:F03 M00004039C:C01 M00001542A:E04 M00003903D:C06 M00003924B:D04 M00001487A:F10 M00003852D:E08 M00004375C:D01 M00001503C:G05 M00003845D:A09 M00001511A:G08 M00003824A:G10 M00001539A:H12 M00003841C:F06 M00001542A:F06 M00003848A:C09 M00001549A:F01 M00003857C:F11 M00001514A:A12 M00003816C:C01 M00001516A:D05 M00003843A:E08 M00001546C:C07 M00003850A:F06 M00001549A:H11 M00003813B:A11 M00001538A:D03 M00003855C:F10 M00001544A:C09 M00003850D:B05 M00001546B:F12 M00003841D:F06 M00001550A:D09 M00003858B:G05 M00001487B:F02 M00003854D:A12 M00001513A:G07 M00003857C:G01 M00001530A:F12 M00003816C:E09 M00001538A:D12 M00003813A:G04 M00001587A:G06 M00003850D:A05 M00001551A:D04 M00001485B:C03

TABLE 38 Clones Deposited on Jan. 22, 1999 cDNA Ref No.; cDNA Library cDNA Ref Ref ES20 No. ES27 cDNA Library Ref ATCC No. 207067 ATCC No. 207074 ATCC No. 207075 Clone M00004891D:A07 M00001623B:G07 M00001550D:H02 Names M00004118B:C11 M00001619D:G05 M00001549C:D02 in M00004105A:B10 M00001616C:C09 M00001549A:A09 Library M00004099A:F11 M00001615C:F03 M00001548A:B11 M00004037C:D07 M00001614D:D09 M00001546C:G10 M00004033D:C05 M00001608B:A03 M00001544C:C06 M00003983D:A09 M00001607D:F07 M00003820B:C05 M00004029B:H08 M00001623D:C10 M00001543A:H12 M00004927A:A02 M00001599B:E09 M00001540C:B10 M00003983C:F10 M00001632C:C09 M00001552B:G05 M00003980B:C06 M00001605C:D12 M00001543C:F01 M00004033D:B07 M00001625D:C07 M00001552D:G08 M00004034C:E08 M00001629B:E06 M00001554B:B07 M00005100B:H07 M00001594A:B12 M00001555A:B01 M00005136A:D10 M00001632C:A02 M00001557A:F01 M00005173D:H02 M00001567C:H12 M00001558A:E11 M00004891D:C11 M00001635C:A03 M00001561C:E11 M00004101A:F07 M00001636C:H09 M00001571D:B11 M00003982B:B06 M00001638A:E07 M00001563B:D11 M00004108C:E01 M00001639A:F10 M00001569C:B06 M00005136D:B07 M00001656C:G08 M00001539B:H06 M00004118D:A11 M00001632A:F12 M00001571B:E03 M00005102C:C01 M00001557A:D02 M00001561D:C11 M00005177C:A01 M00001529B:C04 M00001487C:D06 M00004927C:H11 M00001534B:C12 M00001454B:D08 M00005174D:B02 M00001535D:C01 M00003772D:E10 M00004027A:D06 M00001536D:A12 M00001573C:D03 M00005217A:G10 M00001540B:C09 M00001454D:E05 M00003984A:B06 M00001540D:D02 M00001455D:F09 M00003851C:D07 M00001541C:B07 M00001457C:C11 M00003959C:G06 M00001546B:B02 M00001459B:C09 M00005100B:G11 M00001575B:C09 M00001460A:E01 M00005213C:G01 M00001554B:C07 M00001460C:H02 M00003982B:H07 M00001578D:C04 M00001456A:H02 M00004029C:B03 M00001557C:H07 M00001477B:F04 M00004033D:G06 M00001558B:D08 M00003845D:B04 M00004091B:H09 M00001560D:A03 M00001488A:E01 M00003959D:A04 M00001561C:F06 M00001492D:A11 M00004030D:B06 M00001564D:C09 M00001496C:G10 M00004034C:C06 M00003748B:F02 M00001499A:A05 M00004030C:D12 M00001570D:A03 M00001500A:B02 M00003982C:H10 M00001660C:B12 M00001500D:E10 M00003971C:F09 M00001577B:H02 M00001513D:A03 M00004031B:A06 M00001548A:A08 M00001528A:C11 M00003966B:D02 M00003868B:D12 M00001528C:H04 M00004028B:G08 M00001718D:F07 M00001531B:E09 M00004031C:H10 M00003829C:A11 M00001463A:F06 M00004076D:B09 M00003832B:E01 M00003755A:B03 M00004092D:B11 M00003842B:D09 M00001653B:G07 M00003981C:F05 M00003845A:H12 M00001654D:G11 M00004031D:F05 M00003847B:G03 M00001656B:A07 M00004097B:D03 M00003847C:E09 M00001664B:D06 M00003986D:G07 M00003853D:G08 M00001664C:H10 M00004033B:C02 M00003828A:E04 M00001680B:C01 M00004037B:A04 M00003867C:H09 M00001681A:F03 M00004092C:B12 M00003822A:F02 M00001684B:G03 M00005140D:G09 M00003868C:H10 M00001771A:A07 M00004897D:G05 M00003871A:A05 M00003774C:D02 M00004960B:D12 M00003879C:G10 M00003754D:D02 M00005134C:G04 M00003880C:F10 M00001640B:F03 M00005139A:F01 M00003881D:D06 M00003763B:H01 M00005176A:C12 M00003884D:G07 M00003812C:A05 M00005178A:A07 M00003887A:A06 M00003803C:D09 M00005212A:A02 M00003889A:D10 M00003801B:B10 M00005229D:H07 M00003889D:B09 M00003798D:E03 M00004115C:H04 M00003858D:F12 M00003773B:G01 M00004687A:C03 M00003774B:B08 M00003771A:G10 M00004900C:E11 M00001680D:D02 M00001452A:E07 M00004695B:E04 M00001528A:F09 M00004029B:F11 M00005134D:A06 M00003748A:B07 M00003751B:A05 M00004103B:B07 M00001655A:F06 M00001609B:A11 M00005177A:B06 M00003750A:D01 M00001573D:F10 M00005178A:A08 M00003761D:E02 M00001579C:B11 M00004104D:B05 M00003763D:E10 M00001579C:H10 M00004117B:G01 M00003768A:E02 M00001579D:G07 M00004900D:B10 M00003829B:G03 M00001583B:E10 M00005134D:H03 M00003772A:D07 M00001586D:E02 M00005173C:A02 M00001661B:C08 M00001587D:A10 M00005177A:H09 M00003778A:D08 M00001589A:D12 M00005178B:H01 M00003799A:D09 M00001590C:H08 M00005216C:B09 M00003800A:C09 M00001651B:A11 M00003826B:E11 M00003804A:H04 M00001597A:E12 M00001596A:G06 M00003806D:G05 M00001649C:B10 M00005100B:D02 M00003808C:B05 M00001614A:E06 M00005137A:E01 M00003811A:E03 M00001615C:D02 M00004119A:A06 M00003815D:H09 M00001621D:D03 M00004891D:E07 M00003818B:G12 M00001623D:G03 M00004958B:D01 M00003769B:D03 M00001624A:F09 M00005102C:F09 M00001390A:A09 M00001624C:A06 M00005136D:C01 M00001432A:E06 M00001630B:A11 M00005174D:H02 M00001381A:D02 M00001634B:C10 M00005177C:B04 M00001383A:G04 M00001639D:B07 M00005218B:D09 M00001384C:E03 M00001573D:F04 M00004102C:F03 M00001384C:F12 M00001595B:A09 M00004114B:D09 M00001384D:H07 M00004156B:A12 M00004119D:A07 M00001385B:F10 M00004319D:G09 M00004895C:G05 M00001385C:H11 M00004096A:G02 M00004235A:A12 M00001386A:C02 M00004101C:G08 M00005134B:E01 M00001372C:F07 M00004102A:H02 M00004115C:G03 M00001389D:G11 M00004108A:A09 M00005175B:H04 M00001371D:G01 M00004111D:D11 M00005214B:D11 M00001392C:D10 M00004115D:C08 M00004102D:B05 M00001392D:H06 M00004118D:E08 M00004115A:B12 M00001397B:B09 M00004121C:F06 M00004119D:H06 M00001398A:G03 M00004131B:H09 M00004897D:F03 M00001400A:F06 M00004141D:A09 M00004960B:A09 M00001410B:G05 M00004090A:F09 M00005134C:E11 M00001413A:F02 M00004146A:C08 M00005138B:D12 M00001415B:E09 M00004078B:A11 M00005176A:A05 M00001425A:C11 M00004176B:E08 M00005214C:A09 M00001386A:D11 M00004188C:A09 M00004102C:D01 M00001354C:B06 M00004233C:H09 M00004960B:A08 M00001339D:G02 M00004241D:F11 M00001476D:A09 M00001660A:C12 M00004246C:A09 M00001572A:B06 M00001528A:A01 M00004247C:C12 M00005217D:F12 M00001343D:C04 M00004248B:E08 M00005233A:G08 M00001347B:E01 M00004257C:H06 M00005236B:F10 M00001348A:D04 M00004260D:C12 M00005259B:C01 M00001349C:C05 M00004295B:D02 M00005254D:B08 M00001350A:D06 M00004040D:F01 M00005259C:B05 M00001352D:C05 M00004142D:E10 M00001575A:D06 M00001380C:E05 M00003853D:D03 M00005259D:H08 M00001354B:B10 M00003860D:H07 M00003813C:D08 M00001380C:F02 M00003878C:E04 M00001530D:E06 M00001354C:C10 M00003879A:G05 M00004891B:B12 M00001355B:G11 M00003880B:C08 M00001596B:C11 M00001356D:F06 M00003881A:D09 M00004300C:H09 M00001360D:E11 M00003881C:G09 M00001486D:D12 M00001361C:H11 M00003901B:A05 M00001585D:F03 M00001362C:A10 M00003904D:D10 M00001596B:D09 M00001363C:H02 M00003905C:G10 M00001570D:E06 M00001366D:G02 M00003906B:F12 M00001582C:E01 M00001369A:H12 M00003909A:H04 M00001586C:E06 M00001352D:D02 M00004091B:D11 M00001593B:D10 M00001485D:B10 M00003963A:E03 M00001595C:H11 M00001457B:E03 M00004353C:H07 M00001596B:H05 M00001457C:C12 M00003919A:A10 M00001576A:C11 M00001458C:E01 M00003938A:B04 M00001596C:F09 M00001462B:A10 M00003939C:F04 M00001567A:H05 M00001464D:F06 M00003946D:C11 M00001585D:D11 M00001467D:H05 M00003979A:F03 M00004688A:A02 M00001468B:H06 M00003985C:F01 M00004927A:E06 M00001505C:H01 M00003997B:G07 M00005229D:H09 M00001470A:H01 M00003860D:A01 M00004117B:A12 M00001457A:B07 M00004035A:A04 M00004187D:G09 M00001479B:A01 M00004042D:H02 M00005173B:F01 M00001469D:D02 M00004073B:B01 M00005218A:G05 M00001487A:A05 M00003946A:H10 M00004118A:H08 M00001352C:H02 M00001423D:A09 M00005134A:D11 M00001488D:C10 M00004314B:G07 M00005176C:C09 M00001490C:C12 M00001405D:D11 M00005230D:F06 M00001493B:D09 M00001408A:H04 M00005234D:B04 M00001504D:D11 M00001408D:D04 M00005101C:E09 M00001376B:C06 M00001411D:F05 M00004206A:E02 M00001506B:D09 M00001412A:E04 M00001570C:A05 M00001511B:C06 M00001413A:F03 M00005231A:H04 M00001476B:F10 M00001417B:C04 M00005235A:A03 M00001450D:D04 M00001417D:A04 M00004118B:B04 M00001433A:G07 M00001418B:F07 M00005136D:D06 M00001470C:B10 M00001419D:C10 M00005231C:B01 M00001437D:C04 M00001402B:F12 M00004153B:B03 M00001447C:C01 M00001423A:G05 M00004897C:D06 M00001448B:F06 M00001401C:H03 M00005136D:G06 M00001449D:A06 M00001423D:D12 M00005212B:A02 M00001433B:H11 M00001424B:H04 M00005232A:C10 M00001451D:C10 M00001428B:A09 M00004692A:H10 M00001452A:C07 M00001430A:A02 M00005101C:B09 M00001453C:A11 M00001432D:F05 M00004144A:F04 M00001456B:C09 M00001438B:B09 M00003852B:D11 M00001454B:G03 M00001445B:E04 M00001660D:E05 M00001454B:G07 M00001445C:A08 M00003808A:F09 M00001454C:C08 M00001446C:D09 M00001656A:D10 M00001454C:F02 M00001448A:G09 M00001671A:H06 M00001454D:D06 M00001449C:H12 M00003809C:H07 M00001456B:F10 M00001422C:F12 M00003853C:C06 M00001455D:A09 M00001352C:H10 M00003860A:A08 M00001455D:A11 M00004375A:H01 M00003822B:D08 M00001448D:F09 M00004380B:A05 M00003845A:E12 M00004444B:D11 M00003854C:C02 M00001341A:F12 M00003860B:G09 M00001338B:E02 M00003822B:G01 M00001344A:G07 M00001670A:C11 M00001345A:G11 M00003852A:B03 M00001345B:E10 M00003829D:A11 M00001345C:B01 M00003854C:F01 M00001346B:B07 M00003856B:C04 M00001405B:E09 M00003905A:H11 M00001352B:F04 M00001530A:F11 M00001451C:E01 M00003840B:E07 M00001361A:H07 M00003905B:G03 M00001362B:H06 M00003840B:E08 M00001372C:G12 M00003855A:C12 M00001375B:G12 M00003905B:H05 M00001376A:C05 M00003826B:B04 M00001376B:A08 M00003851C:B06 M00001377C:E12 M00003853B:C08 M00001382B:F12 M00003829A:F03 M00001385A:F12 M00001638C:G01 M00001394A:E04 M00003845D:B02 M00001395A:C09 M00001653B:G07 M00001396A:H03 M00001578B:A02 M00001350B:G11 M00001590B:H10 M00001595C:A09 M00001596A:E07 M00001607A:B06 M00001607A:D10 M00001652C:B09 M00001671B:F02 M00001632C:D08 M00001638C:H07 M00001652D:B09 M00001614C:E11 M00001633B:B11 M00001651C:A04 M00001639D:G12 M00001671C:F11 M00001638A:B04 M00001637C:H12 M00001669B:H06 M00001639D:F02 M00001590A:C08 M00001636A:C02 M00001614A:A04 M00001639D:G06

TABLE 39 Library Deposited on Jan. 22, 1999 cDNA Ref No.; cDNA Library Ref ES29 cDNA Library Ref ES30 ATCC Accession No. ATCC No. 207076 ATCC No. 207077 Clone Names in M00001449D:B01 M00001594D:B08 Library M00001476D:F03 M00001593A:B07 M00001456C:B12 M00001594A:C01 M00001469B:B01 M00001594A:D08 M00001471A:B04 M00001594A:G09 M00001472A:D08 M00001595C:B05 M00001473A:A07 M00001594B:F12 M00001473C:D09 M00001596D:E03 M00001475B:C04 M00001594D:C03 M00001475C:G11 M00001592C:F11 M00001476A:D11 M00001590D:G07 M00001476B:D10 M00001595D:A04 M00001468A:C05 M00001595D:G03 M00001476C:C11 M00001601A:A06 M00001467A:H07 M00001590C:F10 M00001477B:E02 M00001589B:B08 M00001478B:H08 M00001589C:E06 M00001479C:E01 M00001611B:A05 M00001480A:D03 M00001601A:E02 M00001480C:A05 M00001587A:D01 M00001481A:H08 M00001591B:B12 M00001481B:D09 M00001590B:G08 M00001482A:H05 M00001592C:E05 M00001482D:H11 M00001591B:B06 M00001483C:G09 M00001591D:C07 M00001485A:C05 M00001591D:F06 M00001476B:F08 M00001592A:E02 M00001460A:E11 M00001592A:H05 M00001456C:C11 M00001592B:A04 M00001457A:C05 M00001587A:B10 M00001457A:G12 M00001609D:G10 M00001458A:A11 M00005231D:B09 M00001458C:D10 M00001614B:E08 M00001458D:A01 M00005217C:C01 M00001458D:A02 M00001587A:B01 M00001458D:C11 M00001613D:B03 M00001458D:D01 M00001613A:F03 M00001459B:C11 M00001611C:H11 M00001468A:H10 M00001611C:C12 M00001460A:C10 M00001611B:E06 M00001485B:F05 M00001611B:A09 M00001460A:H11 M00001610D:D05 M00001461A:F05 M00001610B:C07 M00001462A:D03 M00001610C:E07 M00001464A:B02 M00001610A:E09 M00001464A:E10 M00001601A:E12 M00001465A:B12 M00001609B:C09 M00001465A:C12 M00001608D:D11 M00001465A:E10 M00001608B:A09 M00001465A:G06 M00001607D:F06 M00001466A:F08 M00001607B:C05 M00001467A:C10 M00001606A:H09 M00001460A:B12 M00001605A:H03 M00001545A:B12 M00001605A:E09 M00001535A:D10 M00001605A:A06 M00001536A:F11 M00001604A:C11 M00001537A:H05 M00001604A:C07 M00001539A:E01 M00001604A:B08 M00001539A:H02 M00001604A:A09 M00001539B:G07 M00001610A:H05 M00001539D:B10 M00005214B:A06 M00001540D:E02 M00005228A:A09 M00001541B:E05 M00001567A:B09 M00001542A:G12 M00001561A:D01 M00001485B:D09 M00001559A:C08 M00001545A:B10 M00001559A:A11 M00001533A:G05 M00001558A:G09 M00001545A:F02 M00001555A:B12 M00001545A:G05 M00001554A:A08 M00001546A:D08 M00001552A:H10 M00001548A:H04 M00001552A:F06 M00001550A:E07 M00005231C:B07 M00001551A:A11 M00005218D:G10 M00001551A:D06 M00001570A:H01 M00001551A:H06 M00005214D:D10 M00001551D:H07 M00001570C:G03 M00001552A:E10 M00005213C:A01 M00001450A:B08 M00005212D:F08 M00001544A:F05 M00005212A:D10 M00001512A:G05 M00005211C:E09 M00001483B:D04 M00005211A:E09 M00001485B:H03 M00005210D:C09 M00001485C:C08 M00005179D:B03 M00001486B:D07 M00005179B:H02 M00001486B:E12 M00005177D:F09 M00001487B:A11 M00005177C:G04 M00001487B:E10 M00005177B:H02 M00001507A:A11 M00001614D:B08 M00001507A:B02 M00001615A:D06 M00001507A:C05 M00005216B:D02 M00001507A:E04 M00001579C:A01 M00001534A:D03 M00001585B:C03 M00001511A:G01 M00001585B:A06 M00001533D:A08 M00001584D:H02 M00001513A:F05 M00001584A:G03 M00001514A:G03 M00001583D:B08 M00001516A:D02 M00001583B:F02 M00001516A:F06 M00001583A:F07 M00001517A:B11 M00001583A:A05 M00001529D:C05 M00001582D:F02 M00001530A:A09 M00001582D:B01 M00001530A:E10 M00001582A:A03 M00001532A:C01 M00001579D:H09 M00001532D:A06 M00001567D:B03 M00001485B:D10 M00001579C:H06 M00001511A:A02 M00001585B:F01 M00004249D:B08 M00001579B:F04 M00004185D:E04 M00001579A:E03 M00004188D:G08 M00001578C:F05 M00004197C:F03 M00001577D:H06 M00004198B:D02 M00001577B:F10 M00004204D:C03 M00001576C:G05 M00004208B:F05 M00001575D:D12 M00004208D:B10 M00001575D:B10 M00004210B:B05 M00001575D:A02 M00001362D:H01 M00001573B:G08 M00004216D:D03 M00001573A:E01 M00004167A:H03 M00001572A:B05 M00004275A:B03 M00001571D:F05 M00004285C:A08 M00001579D:F04 M00004316A:G09 M00001636A:F08 M00004465B:D04 M00001643B:E05 M00004493B:D09 M00001642C:G02 M00001347B:H04 M00001642A:F03 M00001351C:B06 M00001641D:C04 M00001360A:G10 M00001641C:H07 M00004216D:C03 M00001641C:F01 M00004076D:D04 M00001641C:D02 M00001484C:A04 M00001641B:F12 M00001456B:G01 M00001634A:B04 M00003972D:C09 M00001636B:G11 M00003974C:E04 M00001649C:D05 M00003979A:E11 M00001636A:C03 M00003983C:F03 M00001635D:D05 M00003989B:F11 M00001635D:C12 M00004031D:B05 M00001635B:H02 M00004177C:A01 M00001635B:H01 M00004076B:G03 M00001634D:G11 M00004167D:A07 M00001634D:D04 M00004078A:A06 M00001634A:H05 M00004085A:B02 M00001641A:A11 M00004107B:A06 M00001638B:E12 M00004111C:E11 M00001640A:H02 M00004130D:H01 M00001614C:E06 M00004157D:B03 M00001636D:F09 M00004159C:F09 M00001637A:A03 M00004162C:A07 M00001637A:A06 M00004135B:G01 M00001637A:E10 M00004040A:G12 M00001637A:F10 M00001453B:H12 M00001637C:C06 M00001448A:E11 M00001644A:H01 M00001448B:F09 M00001638B:E03 M00001448B:H05 M00001649A:E11 M00001448C:E11 M00001638B:F10 M00001448C:F10 M00001639A:C03 M00001448D:F12 M00001639A:G07 M00001449B:B03 M00001639B:H01 M00001449C:C05 M00001639B:H05 M00001449D:G10 M00001639C:A09 M00001448A:B12 M00001639C:C02 M00001453A:D08 M00001649C:E11 M00001451B:A04 M00001649C:H10 M00001454A:F11 M00001637C:E03 M00001454A:G03 M00001617A:A08 M00001455A:F04 M00001622A:H12 M00001455B:E07 M00001621C:H12 M00001455D:A06 M00001621B:G05 M00001364B:B06 M00001620D:H02 M00004117A:G01 M00001620D:G11 M00001455D:D11 M00001619D:D10 M00001456B:A06 M00001619C:C07 M00001451A:C10 M00001619A:E05 M00001395A:E03 M00001623A:F04 M00001366D:C06 M00001618A:A03 M00001365A:H10 M00001618B:D09 M00001366D:C12 M00001617A:A01 M00001373D:B03 M00001616D:C11 M00001453B:F08 M00001615C:G05 M00001444D:C01 M00001615C:A11 M00001375B:C06 M00001615B:G07 M00001392C:D05 M00001633D:H06 M00001395A:A12 M00001639C:A10 M00001395A:H02 M00001615B:A09 M00001397D:G08 M00001615B:G01 M00001434A:B10 M00001618A:F10 M00001416A:D09 M00001632C:H07 M00001433C:F10 M00001633D:D12 M00001416A:H02 M00001633D:D09 M00001428D:B10 M00001618A:F08 M00001428B:D01 M00001633D:G09 M00001426D:D12 M00001624A:A03 M00001400C:D02 M00001633C:F09 M00001427C:D01 M00001633C:H05 M00001633C:B09 M00001633A:E06 M00001633C:H11 M00001632C:B10 M00001625D:G10 M00001631D:G05 M00001629C:E07 M00001629B:B08 M00001626C:E04 M00001626C:C11 M00001632A:B10 M00001624B:B10 M00001633C:A05 M00001625C:G05

TABLE 40 Clones Deposited on Jan. 22, 1999 cDNA Ref No.; cDNA Library Ref ES31 cDNA Ref No. ES32 cDNA Library Ref ES33 ATCC Accession No. ATCC No. 207078 ATCC No. 207079 ATCC No. 207080 Clone Names in M00003843A:E04 M00003906A:F12 M00005254D:A10 Library M00003842C:G03 M00003906B:H06 M00005260B:E11 M00003842A:A03 M00003906C:C05 M00005260A:F04 M00003841D:A04 M00003907A:F01 M00005260A:A12 M00003841B:E06 M00003907B:C03 M00005259B:D12 M00003841C:H11 M00003907B:D05 M00005257D:H11 M00003844A:A11 M00003918A:D08 M00005257D:G07 M00003841C:F01 M00003918A:F09 M00005257D:A06 M00003841C:H08 M00003918C:H10 M00005257C:G01 M00003841C:D07 M00003924A:D08 M00005257A:H11 M00003844D:A07 M00003958B:E11 M00005236B:H10 M00003845D:G08 M00003958B:H08 M00005236B:G03 M00003852C:B06 M00003960A:G07 M00005257C:E05 M00003854B:A07 M00003971B:A10 M00001608C:D02 M00003854B:D04 M00003972D:H02 M00001608C:G04 M00003859D:C05 M00003973C:C03 M00001608D:F11 M00003860B:F11 M00003974B:B11 M00001609C:A12 M00003867B:G07 M00003974D:F02 M00001609C:G05 M00003867B:G08 M00003974D:H04 M00001610C:B07 M00003841B:E03 M00003975C:F07 M00001612D:D12 M00003822D:B10 M00003977C:A06 M00001612D:F06 M00003867D:A06 M00003977C:B03 M00001613A:D02 M00003868B:G06 M00003977D:A03 M00001614A:B10 M00003867B:D10 M00003977D:A06 M00001614C:G07 M00003831C:G05 M00003977D:D04 M00001615C:E07 M00003901C:B01 M00003978D:G04 M00001625C:F10 M00003868C:C07 M00003980A:F04 M00001626D:A02 M00003820A:A08 M00003980B:C11 M00001629A:H09 M00003820B:D07 M00003981C:B04 M00001629D:B10 M00003820B:D10 M00003982A:B12 M00001629D:D10 M00003822D:C06 M00003982C:G04 M00001630C:F09 M00003823B:F07 M00003984D:B08 M00001631A:D03 M00003824C:D07 M00003985B:G04 M00001631A:F06 M00003825B:B10 M00003985D:E10 M00001631A:F12 M00003825B:B11 M00003986B:A08 M00001631B:H04 M00003828A:D05 M00003986C:D09 M00001633A:F11 M00003822D:D04 M00003986D:C08 M00001633A:G10 M00003830C:A03 M00003987B:E12 M00001633B:A12 M00003840D:H10 M00003987B:F08 M00001633B:E03 M00003832A:A09 M00003987C:G03 M00001633C:A08 M00003833B:B03 M00003988D:A08 M00001633C:E12 M00003833B:C12 M00003989C:D03 M00001635B:B02 M00003834B:G04 M00003989C:G05 M00001636A:H12 M00003835A:A09 M00003989D:F12 M00001638A:C08 M00003835B:H11 M00004029B:F01 M00001638B:C08 M00003835D:G06 M00004029C:C05 M00001639D:C12 M00003837C:E05 M00004029C:G10 M00001640A:F05 M00003837C:F10 M00004030D:F11 M00001642D:G08 M00003839A:D07 M00004034A:A01 M00001647D:G07 M00003839D:E11 M00004034C:G02 M00001649A:E10 M00003829C:H05 M00004034D:E09 M00001650D:D10 M00003901B:C03 M00004035B:H09 M00001650D:F11 M00003878C:F06 M00004036D:B04 M00001651C:D11 M00003878C:G08 M00004036D:B09 M00001651C:G12 M00003879A:A02 M00004038A:F02 M00001652B:D06 M00003879A:B08 M00004038D:G06 M00001652D:G02 M00003879A:C11 M00004039A:C03 M00001652D:G06 M00003879A:D02 M00004039A:H11 M00001653A:A05 M00003879B:G02 M00004039B:A05 M00001653D:H07 M00003880B:D11 M00004039B:E12 M00001654A:E08 M00003880C:E11 M00004040C:A01 M00001654B:A01 M00003880C:H03 M00004051D:E01 M00001654C:D10 M00003901B:F10 M00004072D:F09 M00001654C:G07 M00003890B:C08 M00004073A:D10 M00001654C:G09 M00003877C:A11 M00004075B:G09 M00001655C:C07 M00003819D:B01 M00004076A:D12 M00001655D:E08 M00003901B:G11 M00004076D:H07 M00001655D:H11 M00001692A:G06 M00004078A:C11 M00001656A:H12 M00003903C:C05 M00004078A:E05 M00001656C:C04 M00003903C:E12 M00004078A:F07 M00001656D:C04 M00003903D:C12 M00004078B:C11 M00001657C:C11 M00003903D:D10 M00004078B:F12 M00001657D:A10 M00003903D:H11 M00004079D:G08 M00001659D:A09 M00003904A:C04 M00004081A:E02 M00001661D:D05 M00003904B:C03 M00004081A:G01 M00001664B:E08 M00003904C:A08 M00004081C:A10 M00001664B:F06 M00003881B:F10 M00004083A:E08 M00001669B:C12 M00003871D:G06 M00004083B:C01 M00001669C:B09 M00003868D:D09 M00004086D:G08 M00001670A:F09 M00003868D:D11 M00004087B:A12 M00001678C:F09 M00003870C:A01 M00004087C:A01 M00001693A:H06 M00003870C:A10 M00004088C:F01 M00003805D:E06 M00003870C:E10 M00004088D:A11 M00003806C:A06 M00003871A:A02 M00004088D:B05 M00003809B:A03 M00003871A:B09 M00004088D:B10 M00003810A:A02 M00003871A:C11 M00004090B:B04 M00003810B:B11 M00003871A:G09 M00004090B:H06 M00003810C:B06 M00003871C:E04 M00004092B:E05 M00003810D:H09 M00003871C:F12 M00004093C:C02 M00003811C:C02 M00003878C:D08 M00004096D:H03 M00003813B:F02 M00003871D:E11 M00004099D:F01 M00003813C:H08 M00003877C:G12 M00004100B:C07 M00003813D:B12 M00003875A:A07 M00004103B:E09 M00003813D:C02 M00003875A:B01 M00004105C:B05 M00003813D:G06 M00003875B:F12 M00004105C:C08 M00003814B:C01 M00003875C:A01 M00004107A:A12 M00003817C:A10 M00003875C:A09 M00004107B:D07 M00003817C:G06 M00003875C:G02 M00004108B:B02 M00003817D:D12 M00003876B:C05 M00004108D:E07 M00003821A:H09 M00003876C:D02 M00004108D:G04 M00003822B:G12 M00003876C:F02 M00004110A:A10 M00003822C:A07 M00003877B:H10 M00004110B:A07 M00003823C:B01 M00003868D:B09 M00004118B:A03 M00003823C:C04 M00003871D:A10 M00004118B:F01 M00003824A:G11 M00001669D:D06 M00004118D:B05 M00003824B:C09 M00001661A:B11 M00004119A:C09 M00003824C:A10 M00001661B:F06 M00004136D:B02 M00003824D:D08 M00001662A:C07 M00004137A:D06 M00003825B:F10 M00001662A:G01 M00004139C:A12 M00003825D:F01 M00001662B:F06 M00004149C:B02 M00003826C:F05 M00001663C:F12 M00004159C:G12 M00003829A:B08 M00001664A:F08 M00004169D:B11 M00003829C:E08 M00001664D:F04 M00004187D:H06 M00003829D:D12 M00001661A:E06 M00004228C:H03 M00003829D:F03 M00001669A:B02 M00004244C:G07 M00003830D:B11 M00001669B:B12 M00004358D:C02 M00003830D:H11 M00001669C:C08 M00004690A:G08 M00003833D:H08 M00001675A:G10 M00004891B:D01 M00003833D:H10 M00001669D:C03 M00004891C:D04 M00003840A:C10 M00001660B:E03 M00004895B:E12 M00003840B:F05 M00001669D:F05 M00004895B:G04 M00003840C:C02 M00001670B:G12 M00004895D:G07 M00003845C:D04 M00001671A:A10 M00004898C:F03 M00003845D:A04 M00001671B:G05 M00004899D:G06 M00003846B:C05 M00001671C:C11 M00004959D:H12 M00003846C:F08 M00001672D:E08 M00004960A:B08 M00003848B:E07 M00001673A:G08 M00004960C:E10 M00003848D:G02 M00001673B:B07 M00005100A:B02 M00003850C:G09 M00001673B:F07 M00005100A:C01 M00003851A:A06 M00001673D:D06 M00005101C:E12 M00003851B:D03 M00001673D:F10 M00005102C:D03 M00003851B:E01 M00001674A:G07 M00005134B:E08 M00003851C:F09 M00001692D:B01 M00005139A:H03 M00003851D:H11 M00001669C:D09 M00005140C:B10 M00003852B:G04 M00001655C:E01 M00005140D:C06 M00003852C:F07 M00001649D:A08 M00005178D:H04 M00003853B:C10 M00001650A:C11 M00005210A:E06 M00003854C:C09 M00001651A:H11 M00005212B:E01 M00003855A:A01 M00001652A:A01 M00005212C:C03 M00003855A:F01 M00001652B:G10 M00005212C:D02 M00003855B:B09 M00001652D:E05 M00005212C:H02 M00003856A:G04 M00001652D:E09 M00005212D:D09 M00003856B:A12 M00001653B:C06 M00005212D:H01 M00003857A:E12 M00001653B:G10 M00005216A:D09 M00003857A:H10 M00001653C:D10 M00005216A:H01 M00003857C:E05 M00001654D:A03 M00005217B:A06 M00003858B:G02 M00001654D:E12 M00005218A:F09 M00003860D:E06 M00001654D:F11 M00005228A:B03 M00003905C:F12 M00001660C:B06 M00005228C:C05 M00003911A:D12 M00001658D:G12 M00005229B:G12 M00003966B:A04 M00001675C:A04 M00005229B:H04 M00003966C:A12 M00001660B:D03 M00005229B:H06 M00003966C:F03 M00001660B:A09 M00005229D:H03 M00003973D:F08 M00001659D:C09 M00005230B:H09 M00003974D:E01 M00001659D:B05 M00005232A:H12 M00003974D:H07 M00001654D:F12 M00005233B:D04 M00003976B:E06 M00001659A:D12 M00005233D:H07 M00003976B:H07 M00001655A:B11 M00005235B:F10 M00003978A:E01 M00001658B:A07 M00005236A:E04 M00003978A:E09 M00001658A:G09 M00005236A:G10 M00003978C:A12 M00001657D:A04 M00005236B:A12 M00003980C:E12 M00001657B:B04 M00001448B:A07 M00003980C:F12 M00001656B:E01 M00001448B:G07 M00003981A:A07 M00001660B:E04 M00001448D:E11 M00003981B:B12 M00001659C:F10 M00001455A:D10 M00003982A:G03 M00003808C:A05 M00001455A:E11 M00003982B:C10 M00001694D:C12 M00001476D:F12 M00003982B:H10 M00003746C:E02 M00001478A:F12 M00003983A:D02 M00003779D:E08 M00001482C:F09 M00003983A:F06 M00003792A:B10 M00001485C:D07 M00003983A:G02 M00003793D:A11 M00001485C:G06 M00003983D:E08 M00003794D:G03 M00001485D:A05 M00003983D:H02 M00003797A:C11 M00001487C:A11 M00003985A:C01 M00003797A:D06 M00001487C:G09 M00003986C:G11 M00003797A:G03 M00001530A:B02 M00003986D:H12 M00003800B:F03 M00001530A:H05 M00004027A:A08 M00003805A:F02 M00001530D:A11 M00004028A:B10 M00003806B:C09 M00001539B:B10 M00004028A:G03 M00001674A:G11 M00001567A:C04 M00004029B:A01 M00003806D:D11 M00001567A:C11 M00004029B:A06 M00001693D:E08 M00001567C:B08 M00004029B:G10 M00003808D:D08 M00001567C:E07 M00004029C:F02 M00003809A:C01 M00001570C:B02 M00004029C:F05 M00003809A:F01 M00001570D:E05 M00004030B:A12 M00003809B:B02 M00001570D:E07 M00004030B:D08 M00003809B:E10 M00001573B:A06 M00004030C:A08 M00003813A:B02 M00001573B:H12 M00004030C:C02 M00003813A:D08 M00001575A:D05 M00004034C:F05 M00003813B:E09 M00001575B:C01 M00004035B:F05 M00003814B:C12 M00001576C:H02 M00004036A:A11 M00003814B:F12 M00001577A:A03 M00004037C:D04 M00003815C:C06 M00001578B:A06 M00004038A:E05 M00003815C:D12 M00001579D:F02 M00004038B:D01 M00003817B:C04 M00001582C:C04 M00004039C:E02 M00003806B:G05 M00001582C:G02 M00004039D:B10 M00001679A:D10 M00001584A:A07 M00004040A:A07 M00001675C:C03 M00001584D:B06 M00004040A:B04 M00001675C:D12 M00001584D:C11 M00004040A:C08 M00001675D:E10 M00001585D:B12 M00004040B:C05 M00001676B:B09 M00001586C:H07 M00004040B:F07 M00001676B:E01 M00001589D:A01 M00004069A:E12 M00001676C:A04 M00001590D:B04 M00004069C:C08 M00001676C:E07 M00001592B:B02 M00004077A:G12 M00001676D:A02 M00001592D:H02 M00004085B:G01 M00001676D:B02 M00001594C:E05 M00004087A:B05 M00001677A:G11 M00001594C:H03 M00004090D:F12 M00001677B:A12 M00001594D:G11 M00004092C:D08 M00001677B:B04 M00001595A:C07 M00004097C:E03 M00001677D:B01 M00001595A:D12 M00004097C:H08 M00001678D:B11 M00001595A:E07 M00004097D:B05 M00001681C:A08 M00001595B:G07 M00003819B:G01 M00001595B:G10 M00001693C:E09 M00001595B:H11 M00001693C:C12 M00001595C:A01 M00001692B:E01 M00001595C:A05 M00001692A:B06 M00001595C:B12 M00001678B:H01 M00001595C:E05 M00001681D:C12 M00001595C:E09 M00001694A:E03 M00001595D:C11 M00001680B:D02 M00001596A:A02 M00001680A:B02 M00001596A:D01 M00001679D:F02 M00001596C:G05 M00001679D:B02 M00001607A:A01 M00001679A:G06 Retrieval of Individual Clones from Deposit of Pooled Clones

Where the ATCC deposit is composed of a pool of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

Example 27 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from either human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863), KM12C (Morikawa et al. Cancer Res. (1988) 48:1943-1948), or MDA-MB-231 (Brinkley et al. Cancer Res. (1980) 40:3118-3129) was used to construct a cDNA library from mRNA isolated from the cells. Sequences expressed by these cell lines were isolated and analyzed; most sequences were about 275-300 nucleotides in length. The KM12L4-A cell line is derived from the KM12C cell line. The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246). The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma.

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of 43 sequences. The remaining sequences were then used in a BLASTN vs. GenBank search; sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the GenBank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded. Second, a BLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p value less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 1,565 sequences listed as SEQ ID NOS:6097-7661 in the accompanying Sequence Listing and summarized in Table 41A (inserted prior to claims). Each identified polynucleotide represents sequence from at least a partial mRNA transcript.

Table 41A provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the filing date of the U.S. priority application in which the sequence was first filed; 3) the attorney docket number assigned to the priority application (for internal use); 4) the SEQ ID NO assigned to the sequence in the priority application; 5) the sequence name used as an internal identifier of the sequence; and 6) the name assigned to the clone from which the sequence was isolated. Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene.

In order to confirm the sequences of SEQ ID NOS: 6097-7661, the clones were retrieved from a library using a robotic retrieval system, and the inserts of the retrieved clones re-sequenced. These “validation” sequences are provided as SEQ ID NOS:7662-8706 in the Sequence Listing, and a summary of the “validation” sequences provided in Table 41B (inserted prior to claims). Table 41B provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the sequence name assigned to the “validation” sequence obtained; 3) whether the “validation” sequence contains sequence that overlaps with an original sequence of SEQ ID NOS: 6097-7661 (Validation Overlap (VO)), or whether the “validation” sequence does not substantially overlap with an original sequence of SEQ ID NOS: 6097-7661 (indicated by Validation Non-Overlap (VNO)); and 4) where the sequence is indicated as VO, the name of the clone that contains the indicated “validation” sequence. “Validation” sequences are indicated as “VO” where the “validation” sequence overlaps with an original sequence (e.g., one of SEQ ID NOS: 6097-7661), and/or the “validation” sequence belongs to the same cluster as the original sequence using the clustering technique described above. Because the inserts of the clones are generally longer than the original sequence and the validation sequence, it is possible that a “validation” sequence can be obtained from the same clone as an original sequence but yet not share any of the sequence of the original. Such validation sequences will, however, belong to the same cluster as the original sequence using the clustering technique described above. VO “validation” sequences are contained within the same clone as the original sequence (one of SEQ ID NOS: 6097-7661). “Validation” sequences that provided overlapping sequence are indicating by “VO” can be correlated with the original sequences they validate by referring to Table 41A. Sequences indicated as VNO are treated as newly isolated sequences and may or may not be related to the sequences of SEQ ID NOS: 6097-7661. Because the “validation” sequences are often longer than the original polynucleotide sequences and thus provide additional sequence information. All validation sequences can be obtained either from an indicated clone (e.g., for VO sequences) or from a cDNA library described herein (e.g., using primers designed from the sequence provided in the sequence listing).

Example 28 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS: 7662-8706 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in either the GenBank (nucleotide sequences) or Non-Redundant Protein (amino acid sequences) databases. Query and individual sequences were aligned using the BLAST 2.0 programs, available over the world wide web of the NCBI. (see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above.

Tables 41A and 41B (inserted before the claims) provide the alignment summaries having a p value of 1×10⁻² or less indicating substantial homology between the sequences of the present invention and those of the indicated public databases. Table 41A provides the SEQ ID NO of the query sequence, the accession number of the GenBank database entry of the homologous sequence, and the p value of the alignment. Table 41A provides the SEQ ID NO of the query sequence, the accession number of the Non-Redundant Protein database entry of the homologous sequence, and the p value of the alignment. The alignments provided in Tables 41A and 41B are the best available alignment to a DNA or amino acid sequence at a time just prior to filing of the present specification. The activity of the polypeptide encoded by the SEQ ID NOS listed in Tables 41A and 41B can be extrapolated to be substantially the same or substantially similar to the activity of the reported nearest neighbor or closely related sequence. The accession number of the nearest neighbor is reported, providing a publicly available reference to the activities and functions exhibited by the nearest neighbor. The public information regarding the activities and functions of each of the nearest neighbor sequences is incorporated by reference in this application. Also incorporated by reference is all publicly available information regarding the sequence, as well as the putative and actual activities and functions of the nearest neighbor sequences listed in Table 41 and their related sequences. The search program and database used for the alignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of the corresponding polynucleotide. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of the corresponding polynucleotides.

TABLE 41A Nearest Neighbor (BlastN vs. Genbank) SEQ ID ACC'N DESCRIP. P VALUE 6667 L17043 Homo sapiens pregnancy-specific beta-1-glycoprotein- 1.00E−12 11 gene. 6674 M18864 Rat bone protein I (BP-I) mRNA, partial cds. 7.00E−30 6705 L13838 Human genomic sequence from chromosome 13, 4.00E−36 clone ch13lambdacDNA17–18. 6714 U09646 Human carnitine palmitoyltransferase II precursor 1.00E−34 6723 U72621 Human LOT1 mRNA, complete cds 1.00E−43 6725 M20910 Human 7S L gene, complete. 1.00E−35 6732 Z48950 H. sapiens hH3.3B gene for histone H3.3 4.00E−36 6735 X00247 Human translocated c-myc gene in Raji Burkitt 3.00E−44 lymphoma cells 6739 D80007 Human mRNA for KIAA0185 gene, partial cds 7.00E−52 6742 U14967 Human ribosomal protein L21 mRNA, complete cds. 2.00E−42 6745 M13934 Human ribosomal protein S14 gene, complete cds. 4.00E−45 6748 NM_003902.1 Homo sapiens far upstream element binding protein 1.00E−54 (FUBP) mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 6753 L41142 Homo sapiens signal transducer and activator of 2.00E−62 transcription (STAT5) mRNA, complete cds. 6761 Z12112 pWE15A cosmid vector DNA 2.00E−52 6763 Z54386 H. sapiens CpG island DNA genomic Msel fragment, 7.00E−48 clone 10g3, forward read cpg10g3.ft1a 6764 X80333 M. musculus rab18 mRNA 2.00E−52 6765 X52126 Human alternatively spliced c-myb mRNA 1.00E−64 6767 L26247 Homo sapiens suilisol mRNA, complete cds. 3.00E−54 6772 NM_001736.1 Homo sapiens complement component 5 receptor 1 4.00E−56 C5a anaphylatoxin receptor mRNA, complete cds. 6773 Z50798 G. gallus mRNA for p52 4.00E−55 6775 AB002368 Human mRNA for KIAA0370 gene, partial cds 2.00E−58 6777 M26697 Human nucleolar protein (B23) mRNA, complete cds. 4.00E−48 6779 D42087 Human mRNA for KIAA0118 gene, partial cds 4.00E−56 6789 D50734 Rat mRNA of antizyme inhibitor, complete cds 2.00E−50 6793 X02344 Homo sapiens beta 2 gene 1.00E−67 6794 NM_001067.1 Homo sapiens topoisomerase (DNA) II alpha 7.00E−63 topoisomerase II (top2) mRNA, complete cds. 6797 U36309 Gallus gallus rhoGap protein mRNA, complete cds 3.00E−62 6799 NM_002842.1 Homo sapiens protein tyrosine phosphatase, receptor 2.00E−81 type, H (PTPRH) mRNA > :: dbj|D15049|HUMSAP1C Human mRNA for protein tyrosine phosphatase 6803 U47322 Cloning vector DNA, complete sequence. 1.00E−63 6810 NM_001190.1 Homo sapiens branched chain aminotransferase 2, 4.00E−67 mitochondrial (BCAT2) mRNA > :: gb|U68418|HSU68418 Human branched chain aminotransferase precursor (BCATm) mRNA, nuclear gene encoding mitochondrial protein, complete cds 6814 S62077 HP1Hs alpha = 25 kda chromosomal autoantigen 5.00E−68 [human, mRNA, 876 nt] 6815 U34991 Human endogenous retrovirus clone c18.4, HERV- 2.00E−61 H/HERV-E hybrid multiply spliced protease/integrase mRNA, complete cds, and envelope protein mRNA, partial cds 6818 U18671 Human Stat2 gene, complete cds. 4.00E−77 6819 L18964 Human protein kinase C iota isoform (PRKCI) 4.00E−68 mRNA, complete cds. 6820 D29956 Human mRNA for KIAA0055 gene, complete cds 6.00E−70 6821 M77140 H. sapiens pro-galanin mRNA, 3′ end. 2.00E−72 6824 U51432 Homo sapiens nuclear protein Skip mRNA, complete 1.00E−75 cds 6825 M84334 Macacca mulatta hnRNP A1-gamma isoform mRNA, 5.00E−50 complete cds. 6826 NM_002592.1 Homo sapiens proliferating cell nuclear antigen 1.00E−74 (PCNA) mRNA > :: gb|M15796|HUMCYL Human cyclin protein gene, complete cds. 6827 M88458 Human ELP-1 mRNA sequence. 4.00E−76 6828 U44940 Mus musculus quaking type I (QKI) mRNA, complete 2.00E−69 cds 6829 D17577 Mouse mRNA for kinesin-like protein (Kif1b), 2.00E−71 complete cds 6830 U18920 Human chromosome 17q12–21 mRNA, clone pOV-3, 2.00E−72 partial cds. 6832 M21188 Human insulin-degrading enzyme (IDE) mRNA, 7.00E−82 complete cds. 6833 U49058 Rattus norvegicus CTD-binding SR-like protein rA4 1.00E−67 mRNA, partial cds 6835 D10630 Mus musculus mRNA for zinc finger protein, 4.00E−76 complete cds, clone: CTfin51 6836 U29156 Mus musculus eps15R mRNA, complete cds. 3.00E−84 6837 Y08135 M. musculus mRNA for ASM-like phosphodiesterase 1.00E−86 3a 6838 U90567 Gallus gallus glutamine rich protein mRNA, partial 5.00E−58 cds 6839 U58280 Mus musculus second largest subunit of RNA 4.00E−77 polymerase I (RPA2) mRNA, complete cds 6840 S79539 Pat-12 = Pat-12 product [mice, embryonic stem ES 9.00E−84 cells, mRNA, 2781 nt] 6841 D30666 Rat mRNA for brain acyl-CoA synthetase II, complete 2.00E−89 cds 6842 U29156 Mus musculus eps15R mRNA, complete cds. 2.00E−92 6844 U36909 Bos taurus Rho-associated kinase mRNA, complete e−104 cds 6845 L36315 Mus musculus (clone pMLZ-1) zinc finger protein e−105 6846 X80169 M. musculus mRNA for 200 kD protein e−106 6847 X83577 M. musculus mRNA for K-glypican e−107 7156 Z95437 Human DNA sequence from cosmid A1 on 8.00E−21 chromosome 6 contains ESTs. HERV like retroviral sequence 7208 X69907 H. sapiens gene for mitochondrial ATP synthase c 6.00E−07 subunit (P1 form) 7221 M19390 Bovine interstitial retinol binding protein 8.00E−31 7252 U19247 Homo sapiens interferon-gamma receptor alpha chain 7.00E−41 gene, exon 7 and complete cds 7266 U20239 Mus musculus fibrosin mRNA, partial cds 5.00E−38 7267 D26361 Human mRNA for KIAA0042 gene, complete cds 2.00E−41 7291 NM_000694.1 Homo sapiens aldehyde dehydrogenase 7 (ALDH7) 1.00E−37 mRNA > :: gb|U10868|HSU10868 Human aldehyde dehydrogenase ALDH7 mRNA, complete cds. 7292 U84404 Human E6-associated protein E6-AP/ubiquitin-protein 1.00E−46 ligase (UBE3A) mRNA, alternatively spliced, complete cds 7299 U51714 Human GPI protein p137 mRNA, partial sequence, 3′- 9.00E−53 UTR. 7300 U58884 Mus musculus SH3-containing protein SH3P7 mRNA, 2.00E−49 complete cds. similar to Human Drebrin 7306 X79067 H. sapiens ERF-1 mRNA 3′ end 2.00E−72 7308 U00946 Human clone A9A2BRB5 (CAC)n/(GTG)n repeat- 3.00E−54 containing mRNA 7313 D11078 Homo sapiens RGH2 gene, retrovirus-like element 6.00E−49 7315 U05989 Rattus norvegicus clone par-4 induced by effectors of 3.00E−64 apoptosis mRNA, complete cds. 7316 U13185 Cloning vector pbetagal-Enhancer, complete 3.00E−52 sequence. 7318 D87443 Human mRNA for KIAA0254 gene, complete cds 8.00E−63 7321 U19867 Cloning vector pSPL3, exon splicing vector, complete 7.00E−72 sequence, HIV envelope protein gp 160 and beta- lactamase, complete cds. 7323 U04817 Human protein kinase PITSLRE alpha 2-3 mRNA, 4.00E−57 complete cds. 7326 U03687 Photinus pyralis modified luciferase gene, complete 3.00E−62 cds, and pUC18 derived vector. 7327 U27196 Gallus gallus zinc finger protein (Fzf-1) mRNA, 1.00E−66 complete cds. 7331 X53586 Human mRNA for integrin alpha 6 2.00E−71 7332 J05016 Human (clone pA3) protein disulfide isomerase 3.00E−67 related protein (ERp72) mRNA, complete cds. 7333 M86752 Human transformation-sensitive protein (IEF SSP 1.00E−66 3521) mRNA, complete cds. 7335 L19437 Human transaldolase mRNA containing transposable 5.00E−70 element, complete cds 7337 X90857 H. sapiens mRNA for-14 gene, containing globin 1.00E−74 regulatory element 7338 NM_003980.1 Homo sapiens microtubule associated protein 7 9.00E−76 mRNA 7341 U17901 Rattus norvegicus phospholipase A-2-activating 3.00E−75 protein (plap) mRNA, complete cds. 7342 S80632 threonine, tyrosine phosphatase [human, brain, mRNA 2.00E−69 Partial, 1236 nt] 7343 M76541 Human DNA-binding protein (NF-E1) mRNA, 2.00E−80 complete cds. 7344 S55305 14-3-3 protein gamma subtype = putative protein kinase 7.00E−93 C regulatory protein [rats, brain, mRNA, 3410 nt] > :: dbj|D17447|D17447 Rattus norvegicus mRNA for 14- 3-3 protein gamma-subtype, complete cds 7345 NM_002350.1 Homo sapiens v-yes-1 Yamaguchi sarcoma viral 3.00E−86 related oncogene homolog (LYN) mRNA > :: gb|M16038|HUMLYN Human lyn mRNA encoding a tyrosine kinase. 7346 Y10725 M. musculus mRNA for protein kinase KIS 4.00E−68 7347 U89931 Cloning vector pTRE, complete sequence 3.00E−65 7348 Z46386 Bovine herpesvirus type 4 DNA for nonconserved 3.00E−73 region F (DN599 like strain) 7349 L77599 Homo sapiens (clone SEL214) 17q YAC (303G8) 2.00E−69 RNA. 7351 Y10746 H. sapiens mRNA for protein containing MBD 1 2.00E−79 7352 L77599 Homo sapiens (clone SEL214) 17q YAC (303G8) 2.00E−71 RNA. 7353 Z57619 H. sapiens CpG island DNA genomic Mse1 fragment, 7.00E−72 clone 187a6, forward read cpg187a6.ft1b 7354 U48807 Human MAP kinase phosphatase (MKP-2) mRNA, 3.00E−76 complete cds 7356 M27444 Bos taurus (clone pTKD7) dopamine and cyclic AMP- 4.00E−76 regulated neuronal phosphoprotein (DARPP-32) mRNA, complete cds. 7357 U37150 Bos taurus peptide methionine sulfoxide reductase 5.00E−78 (msrA) mRNA, complete cds 7358 U02435 Cloning vector pSVbeta, complete sequence 1.00E−77 7359 U09662 Cloning vector pSEAP-Enhancer, complete sequence 4.00E−79 7360 M99566 sCos cloning vector SfiI containing bacteriophage 1.00E−79 promoters and flanking restriction sites in sCos vectors. 7362 Z12112 pWE15A cosmid vector DNA 4.00E−80 7363 U55387 Cricetulus griseus SL15 mRNA, complete cds 2.00E−82 7365 L14684 Rattus norvegicus nuclear-encoded mitochondrial 2.00E−91 elongation factor G mRNA, complete cds. 7366 U49057 Rattus norvegicus CTD-binding SR-like protein rA9 7.00E−93 mRNA, complete cds 7367 U57368 Mus musculus EGF repeat transmembrane protein 4.00E−97 mRNA, complete cds. 7368 AF000938 Mus musculus RNA polymerase I largest subunit 8.00E−94 7370 X80169 M. musculus mRNA for 200 kD protein e−102 7371 U09874 Mus musculus SKD3 mRNA, complete cds. e−105 7372 D78020 Rat mRNA for NFI-A4, partial cds e−108 7611 Z73360 Human DNA sequence from cosmid 92M18, BRCA2 9.00E−22 gene region chromosome 13q12–13 7618 X62078 H. sapiens mRNA for GM2 activator protein 7.00E−72 7619 X85750 H. sapiens mRNA for transcript associated with 2.00E−50 monocyte to macrophage differentiation 7621 X03473 Human gene for histone H1(0) 1.00E−67 7631 X64411 R. norvegicus mRNA for 100 kDa protein 1.00E−54 7634 X13345 Human gene for plasminogen activator inhibitor 1 2.00E−59 7638 D86971 Human mRNA for KIAA0217 gene, partial cds 7.00E−83 7639 NM_001859.1 Homo sapiens solute carrier family 31 7.00E−72 gb|U83460|HSU83460 Human high-affinity copper uptake protein (hCTR1) mRNA, complete cds 7640 X68194 H. sapiens h-Sp1 mRNA 5.00E−57 7641 AB002326 Human mRNA for KIAA0328 gene, partial cds 3.00E−74 7644 D31762 Human mRNA for KIAA0057 gene, complete cds 3.00E−85 7646 X58472 Mouse KIN17 mRNA for kin17 protein 2.00E−57 7647 U13185 Cloning vector pbetagal-Enhancer, complete 2.00E−79 sequence. 7648 U55939 Expression vector pVP-Nco, complete sequence. 1.00E−76 7649 D87671 Rattus norvegicus mRNA for TIP120, complete cds 1.00E−87 7650 U25691 Mus musculus lymphocyte specific helicase mRNA, 4.00E−86 complete cds 7651 U55939 Expression vector pVP-Nco, complete sequence. 5.00E−79 7652 Z12112 pWE15A cosmid vector DNA 2.00E−79 7653 U13185 Cloning vector pbetagal-Enhancer, complete 2.00E−79 sequence. 7654 U13185 Cloning vector pbetagal-Enhancer, complete 6.00E−80 sequence. 7655 Z12112 pWE15A cosmid vector DNA 6.00E−80 7656 U09661 Cloning vector pSEAP-Control, complete sequence 6.00E−80 7657 U36909 Bos taurus Rho-associated kinase mRNA, complete 2.00E−90 cds 7658 L36610 Mus musculus protein synthesis initiation factor 4A 2.00E−71 (elF-4A) gene, exons 5, 6, 7, 8, and 9. 7659 S79463 M-Sema F = a factor in neural network development 1.00E−85 7660 U35312 Mus musculus nuclear receptor co-repressor mRNA, 1.00E−98 complete cds 7667 L32977 Homo sapiens (clone f17252) ubiquinol cytochrome c 0 reductase Rieske iron-sulphur protein (UQCRFS1) gene, exon 2 7672 S78454 Mus musculus metal response element DNA-binding 0 protein M96 mRNA, complete cds 7682 M88458 Human ELP-1 mRNA sequence. 0 7718 S77512 LAMB2 = laminin beta 2 chain [human, placenta, e−131 mRNA, 5642 nt] 7720 X53305 H. sapiens mRNA for stathmin 0 7721 J03591 Human ADP/ATP translocase mRNA, 3′ end, clone 0 pHAT3. 7726 L18964 Human protein kinase C iota isoform (PRKCI) 2E−67 mRNA, complete cds. 7736 D29956 Human mRNA for KIAA0055 gene, complete cds 0 7745 M26697 Human nucleolar protein (B23) mRNA, complete cds. e−149 7765 U47322 Cloning vector DNA, complete sequence. 4E−65 7785 NM_002079.1 Homo sapiens glutamic-oxaloacetic transaminase 1, 0 soluble (aspartate aminotransferase 1) aspartate aminotransferase mRNA, complete cds. 7789 U55939 Expression vector pVP-Nco, complete sequence. 2E−70 7790 D80007 Human mRNA for KIAA0185 gene, partial cds 0 7791 NM_001904.1 Homo sapiens catenin (cadherin-associated protein), e−108 beta 1 (88 kD) (CTNNB1) mRNA > :: emb|X87838|HSRNABECA H. sapiens mRNA for beta-catenin 7797 U19867 Cloning vector pSPL3, exon splicing vector, complete 1E−44 sequence, HIV envelope protein gp160 and beta- lactamase, complete cds. 7798 M31061 Human ornithine decarboxylase gene, complete cds. 0 7817 Z96177 H. sapiens telomeric DNA sequence, clone 2E−70 10QTEL040, read 10QTELOO040.seq 7818 NM_001904.1 Homo sapiens catenin (cadherin-associated protein), e−176 beta 1 (88 kD) (CTNNB1) mRNA > :: emb|X87838|HSRNABECA H. sapiens mRNA for beta-catenin 7854 X83577 M. musculus mRNA for K-glypican 0 7857 S79539 Pat-12 = Pat-12 product [mice, embryonic stem ES e−176 cells, mRNA, 2781 nt] 7869 L38951 Homo sapiens importin beta subunit mRNA, complete 1E−78 cds 7872 NM_003902.1 Homo sapiens far upstream element binding protein 0 (FUBP) mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 7887 L08783 BlueScribe M13 Plus cloning vector. 0 7905 U86751 Human nucleolar fibrillar center protein (ASE-1) 8E−95 mRNA, complete cds 7913 M21188 Human insulin-degrading enzyme (IDE) mRNA, e−134 complete cds. 7927 NM_001614.1 Homo sapiens actin, gamma 1 (ACTG1) mRNA > :: 0.00E+00 emb|X04098|HSACTCGR Human mRNA for cytoskeletal gamma-actin 7932 U12404 Human Csa-19 mRNA, complete cds. 0 7933 X79236 H. sapiens rps26 gene e−145 7934 NM_003313.1 Homo sapiens tissue specific transplantation antigen 0 P35B (TSTA3) mRNA > :: gb|U58766|HSU58766 Human FX protein mRNA, complete cds 7935 M27436 Human tissue factor gene, complete cds, with a Alu e−121 repetitive sequence in the 3′ untranslated region. > :: gb|I05724| Sequence 12 from Patent EP 0278776 7945 X79067 H. sapiens ERF-1 mRNA 3′ end 0 7946 NM_003017.1 Homo sapiens splicing factor, arginine/serine-rich 3 e−135 (SFRS3) mRNA > :: gb|L10838|HUMSRP20 Homo sapiens SR protein family, pre-mRNA splicing factor (SRp20) mRNA, complete cds. 7953 U48807 Human MAP kinase phosphatase (MKP-2) mRNA, 0.00E+00 complete cds 7954 U48807 Human MAP kinase phosphatase (MKP-2) mRNA, 0.00E+00 complete cds 7969 U04817 Human protein kinase PITSLRE alpha 2–3 mRNA, 8.00E−53 complete cds. 7972 U18297 Human MST1 (MST1) mRNA, complete cds. 0.00E+00 7973 NM_001859.1 Homo sapiens solute carrier family 31 0 gb|U83460|HSU83460 Human high-affinity copper uptake protein (hCTR1) mRNA, complete cds 7985 X70272 single stranded replicative centromeric Saccharomyces 3.00E−76 cerevisiae/E. coli shuttle vector 7993 L26050 Human mitochondrial 2,4-dienoyl-CoA reductase 0.00E+00 mRNA, complete cds. 7995 X06747 Human hnRNP core protein A1 e−157 7997 M64571 Human microtubule-associated protein 4 mRNA, 0.00E+00 complete cds. 8004 X65322.1 Cloning vector pCAT-Basic 9.00E−53 8009 NM_002654.1 Homo sapiens pyruvate kinase, muscle (PKM2) e−159 mRNA > :: gb|M23725|HUMPKM2L Human M2- type pyruvate kinase mRNA, complete cds. 8012 U49352 Human liver 2,4-dienoyl-CoA reductase mRNA, 2.00E−71 complete cds 8022 D31889 Human mRNA for KIAA0072 gene, partial cds > :: e−167 gb|G27027|G27027 human STS SHGC-31585. 8037 U43944 Human breast cancer cytosolic NADP(+)-dependent 1.00E−89 malic enzyme mRNA, partial cds 8067 U83659 Human multidrug resistance-associated protein 3.00E−85 homolog (MRP3) mRNA, partial cds 8092 M33519 Human HLA-B-associated transcript 3 (BAT3) 3.00E−84 mRNA, complete cds. 8093 U55387 Cricetulus griseus SL15 mRNA, complete cds e−150 8114 L36315 Mus musculus (clone pMLZ-1) zinc finger protein e−162 8121 NM_003902.1 Homo sapiens far upstream element binding protein e−175 (FUBP) mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 8128 X56932 H. sapiens mRNA for 23 kD highly basic protein 0.00E+00 8135 X98654 H. sapiens mRNA for DRES9 protein 9.00E−97 8146 S62077 HP1Hs alpha = 25 kda chromosomal autoantigen 4.00E−68 [human, mRNA, 876 nt] 8153 M23619 Human HMG-I protein isoform mRNA (HMGI gene), e−117 clone 6A. 8173 NM_003217.1 Homo sapiens testis enhanced gene transcript 4E−99 8188 U18671 Human Stat2 gene, complete cds. 0.00E+00 8192 D43636 Human mRNA for KIAA0096 gene, partial cds 0 8194 NM_002734.1 Homo sapiens protein kinase, cAMP-dependent, 0 regulatory, type I, alpha (tissue specific extinguisher 1) (PRKAR1A) mRNA > :: gb|M33336|HUMCAMPPK Human cAMP-dependent protein kinase type I-alpha subunit 8195 U72621 Human LOT1 mRNA, complete cds 0.00E+00 8208 NM_003902.1 Homo sapiens far upstream element binding protein 0.00E+00 (FUBP) mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 8214 L41142 Homo sapiens signal transducer and activator of 0.00E+00 transcription (STAT5) mRNA, complete cds. 8215 Z48950 H. sapiens hH3.3B gene for histone H3.3 0.00E+00 8249 L09260 Human (chromosome 3p25) membrane protein e−100 mRNA. 8254 X65304.1 Cloning vector pGEM-3Z e−173 8259 NM_003358.1 Homo sapiens UDP-glucose ceramide e−141 glucosyltransferase (UGCG) mRNA > :: dbj|D50840|HUMCGA Homo sapiens mRNA for ceramide glucosyltransferase, complete cds > :: dbj|E12454|E12454 cDNA encoding human ceramide glucosyltransferase 8275 M95605 Bos taurus S-adenosylmethionine decarboxylase e−175 8276 M12623 Human non-histone chromosomal protein HMG-17 0.00E+00 mRNA, complete cds. 8277 U79143 Human phosphoinositide 3′-hydroxykinase p110-alpha 0.00E+00 subunit mRNA, complete cds 8288 K01906 Human fetal liver c-myc proto-oncogene, exon 3 and e−165 flanks. 8290 X74870 H. sapiens gene for RNA pol II largest subunit, exons e−161 23–29 8331 L16991 Human thymidylate kinase (CDC8) mRNA, complete 0.00E+00 cds. 8353 L08783 BlueScribe M13 Plus cloning vector. 0.00E+00 8372 NM_002245.1 Homo sapiens potassium inwardly-rectifying channel, 0 subfamily K, member 1 (KCNK1) mRNA > :: gb|U33632|HSU33632 Human two P-domain K+ channel TWIK-1 mRNA, complete cds. 8374 D50734 Rat mRNA of antizyme inhibitor, complete cds e−157 8375 U26401 Human galactokinase (galK) mRNA, complete cds. > 0.00E+00 8381 U49058 Rattus norvegicus CTD-binding SR-like protein rA4 e−138 mRNA, partial cds 8383 X65306.1 Cloning vector pGEM-3Zf(+) e−116 8395 NM_001172.1 Homo sapiens arginase, type II (ARG2) mRNA > :: e−127 gb|U82256|HSU82256 Homo sapiens arginase type II mRNA, complete cds 8405 M25160 Human Na, K-ATPase beta subunit (ATP1B) gene, 0.00E+00 exons 3 through 6. 8411 Y08736 H. sapiens vegf gene, 3′UTR 1.00E−78 8416 U13737 Human cysteine protease CPP32 isoform alpha 0.00E+00 mRNA, complete cds. 8419 Y08135 M. musculus mRNA for ASM-like phosphodiesterase e−148 3a 8420 Y08135 M. musculus mRNA for ASM-like phosphodiesterase 0 3a 8424 NM_001677.1 Homo sapiens ATPase, Na+/K+ transporting, beta 1 1E−77 polypeptide (ATP1B1) mRNA > :: emb|X03747|HSATPBR Human mRNA for Na/K− ATPase beta subunit 8433 Y08135 M. musculus mRNA for ASM-like phosphodiesterase e−168 3a 8460 U54778 Human 14-3-3 epsilon mRNA, complete cds 1E−67 8461 Y08135 M. musculus mRNA for ASM-like phosphodiesterase 0 3a 8464 NM_001172.1 Homo sapiens arginase, type II (ARG2) mRNA > :: e−127 gb|U82256|HSU82256 Homo sapiens arginase type II mRNA, complete cds 8481 AB002293 Human mRNA for KIAA0295 gene, partial cds 0 8490 M21188 Human insulin-degrading enzyme (IDE) mRNA, 2E−81 complete cds. 8521 D87466 Human mRNA for KIAA0276 gene, partial cds 1E−97 8525 U58884 Mus musculus SH3-containing protein SH3P7 mRNA, 4E−96 complete cds. similar to Human Drebrin 8537 AB005216 Homo sapiens mRNA for Nck, Ash and phospholipase 0 C gamma-binding protein NAP4, partial cds 8538 NM_001960.1 Homo sapiens eukaryotic translation elongation factor 0.00E+00 1 delta (guanine nucleotide exchange protein) (EEF1D) mRNA > :: emb|Z21507|HSEF1DELA H. sapiens EF-1delta gene encoding human elongation factor-1-delta 8540 M92449 Human LTR mRNA, 3′ end of coding region and 3′ e−143 flank. 8548 NM_003350.1 Homo sapiens ubiquitin-conjugating enzyme E2 0 variant 2 (UBE2V2) mRNA > :: emb|X98091|HSVITDITR H. sapiens mRNA for protein induced by vitamin D 8552 U44975 Homo sapiens DNA-binding protein CPBP (CPBP) 5.00E−69 mRNA, partial cds 8555 Z84510 H. sapiens flow-sorted chromosome 6 HindIII 4.00E−66 fragment, SC6pA28B7 8559 Z48042 H. sapiens mRNA encoding GPI-anchored protein e−172 p137 8593 U32986 Human xeroderma pigmentosum group E UV- 0 damaged DNA binding factor mRNA, complete cds. 8611 NM_003419.1 Homo sapiens zinc finger protein 10 (KOX 1) for zinc e−129 finger protein 8616 Y00711 Human mRNA for lactate dehydrogenase B (LDH-B) 0.00E+00 8622 Y10725 M. musculus mRNA for protein kinase KIS 0.00E+00 8639 X62078 H. sapiens mRNA for GM2 activator protein e−164 8644 NM_001009.1 Homo sapiens ribosomal protein S5 (RPS5) mRNA 0.00E+00 complete cds. 8652 U97188 Homo sapiens putative RNA binding protein KOC 1E−86 8671 NM_002852.1 Homo sapiens pentaxin-related gene, rapidly induced 0.00E+00 by IL-1 beta (PTX3) mRNA > :: emb|X63613|HSPTX3R H. sapiens mRNA for pentaxin (PTX3) 8674 X67155 H. sapiens mRNA for mitotic kinesin-like protein-1 0.00E+00 8684 M54968 Human K-ras oncogene protein mRNA, complete cds> e−123 8687 D88687 Homo sapiens mRNA for KM-102-derived reductase- 0 like factor, complete cds 8689 NM_001436.1 Homo sapiens fibrillarin (FBL) mRNA > :: e−103 gb|M59849|HUMFIBAA Human fibrillarin (Hfib1) mRNA, complete cds. 8691 AB002326 Human mRNA for KIAA0328 gene, partial cds 0.00E+00 8694 M11948 Human promyelocytic leukemia cell mRNA, clones 9.00E−84 pHH58 and pHH81.

TABLE 41B Nearest Neighbor (BlastX vs. Non-Redundant Proteins) P SEQ ID ACC'N DESCRIP. VALUE 6133 4239895 (AB016816) MASL1 [Homo sapiens] 9.00E−54 6162 4514653 (AB024057) vascular Rab-GAP/TBC-containing 6.00E−55 protein [Homo sapiens] 6174 4454524 (AC004841) similar to insulin receptor substrate 6.00E−22 BAP2; similar to PID: g4126477 [Homo sapiens] 6175 4545264 (AF118240) peroxisomal biogenesis factor 16 [Homo 1.00E−45 sapiens] 6208 3413938 (AB007963) KIAA0494 protein [Homo sapiens] 3.00E−44 6218 4239895 (AB016816) MASL1 [Homo sapiens] 1.00E−47 6235 4502371 breast cancer antiestrogen resistance 3 >gi|3237306 2.00E−44 (U92715) breast cancer antiestrogen resistance 3 protein [Homo sapiens] 6250 4586880 (AB017114) AD 3 [Homo sapiens] 4.00E−48 6253 3327170 (AB014578) KIAA0678 protein [Homo sapiens] 2.00E−51 6264 3153241 (AF053004) class I cytokine receptor [Homo sapiens] 2.00E−17 6267 4138233 (AJ007780) parp-2 gene [Mus musculus] 2.00E−32 6270 3287173 (AJ006266) AND-1 protein [Homo sapiens] 2.00E−42 6283 4507145 UNKNOWN >gi|3873216 (AF065485) sorting nexin 4 8.00E−46 [Homo sapiens] 6303 4153860 (AC005074) similar to U47321 (PID: g1245146) 4.00E−15 [Homo sapiens] 6320 3236430 (AF067379) ubiquitin-protein ligase E3-alpha [Mus 3.00E−35 musculus] 6349 3043696 (AB011158) KIAA0586 protein [Homo sapiens] 1.00E−44 6356 4519623 (AB017616) homologous to the yeast YGR163 gene 2.00E−54 [Mus musculus] 6376 4455035 (AF116238) pseudouridine synthase 1 [Homo sapiens] 4.00E−48 6400 3075377 (AC004602) F23487_2 [Homo sapiens] 2.00E−21 6402 4505611 poly(A)-specific ribonuclease 7.00E−41 6469 1825606 (U88169) similar to molybdoterin biosynthesis MOEB 2.00E−37 proteins [Caenorhabditis elegans] 6478 4586287 (AB004794) DUF140 [Xenopus laevis] 7.00E−45 6492 3941342 (AF043250) mitochondrial outer membrane protein 5.00E−40 [Homo sapiens] >gi|3941347 (AF043253) mitochondrial outer membrane protein [Homo sapiens] >gi|4105703|gb|AAD02504| 6510 4586844 (AB015633) type II membrane protein 2.00E−46 6518 3327078 (AB014532) KIAA0632 protein [Homo sapiens] 6.00E−36 6529 3327230 (AB014608) KIAA0708 protein [Homo sapiens] 5.00E−52 6568 3372677 (AF061749) tumorous imaginal discs protein Tid56 7.00E−35 homolog 6598 4050034 (AF098482) transcriptional coactivator p52 [Homo 1.00E−36 sapiens] 6600 4406632 (AF131801) Unknown [Homo sapiens] 3.00E−21 6608 3114828 (AJ005897) JM5 [Homo sapiens] 3.00E−44 6626 3766209 (AF071777) IRE1 [Mus musculus] 2.00E−29 6657 3043644 (AB011132) KIAA0560 protein [Homo sapiens] 3.00E−43 6668 3088575 (AF059531) protein arginine N-methyltransferase 3 4.00E−46 [Homo sapiens] 6674 4505891 UNKNOWN >gi|3153235 (AF046889) lysyl 3.00E−30 hydroxylase isoform 3 [Homo sapiens] >gi|3551836 6686 3114828 (AJ005897) JM5 [Homo sapiens] 1.00E−24 6688 3242214 (AJ006778) DRIM protein [Homo sapiens] 2.00E−36 6694 4200236 (AL035308) hypothetical protein [Homo sapiens] 8.00E−09 6696 3413892 (AB007934) KIAA0465 protein [Homo sapiens] 2.00E−51 6731 3043626 (AB011123) KIAA0551 protein [Homo sapiens] 3.00E−31 6739 2498864 RRP5 PROTEIN HOMOLOG (KIAA0185) 3.00E−13 hypothetical protein YM9959.11C of S. cerevisiae. [Homo sapiens] 6766 3402197 (AJ010014) M96A protein [Homo sapiens] 1.00E−21 6773 2217964 (Z50798) p52 [Gallus gallus] 7.00E−14 6782 3043626 (AB011123) KIAA0551 protein [Homo sapiens] 1.00E−40 6793 135470 TUBULIN BETA-5 CHAIN sapiens] 3.00E−21 6797 3327056 (AB014521) KIAA0621 protein [Homo sapiens] 2.00E−29 6800 4506787 UNKNOWN GTPASE-ACTIVATING-LIKE 4.00E−41 PROTEIN IQGAP1 (P195) (KIAA0051) protein - human >gi|473931|dbj|BAA06123| (D29640) KIAA0051 [Homo sapiens] >gi|536844 (L33075) ras GTPase-activating-like protein [Homo sapiens] 6805 1350762 60S RIBOSOMAL PROTEIN L6 sapiens] 2.00E−22 6809 2687400 (AF035824) vesicle soluble NSF attachment protein 1.00E−23 receptor [Homo sapiens] 6826 2914385 Chain C, Human Pcna >gi|2914387|pdb|1AXC|E 2.00E−27 Chain E, Human Pcna 6827 284076 ERD-2-like protein, ELP-1 - human 1.00E−26 6829 2497524 KINESIN-LIKE PROTEIN KIF1B mouse 9.00E−33 >gi|407339|dbj|BAA04503| (D17577) Kif1b [Mus musculus] 6831 3327056 (AB014521) KIAA0621 protein [Homo sapiens] 1.00E−13 6832 279567 insulinase (EC 3.4.99.45) - human 2.00E−26 6834 487416 (L20302) actin filament protein [Gallus gallus] 3.00E−45 6835 1731428 ZINC FINGER PROTEIN ZFP-38 7.00E−35 6836 968973 (U29156) involved in signaling by the epidermal 1.00E−22 growth factor receptor; Method: conceptual translation supplied by author. [Mus musculus] 6837 1552350 (Y08135) acid sphingomyelinase-like 2.00E−35 phosphodiesterase [Mus musculus] 6838 3327098 (AB014542) KIAA0642 protein [Homo sapiens] 3.00E−15 6839 3914801 DNA-DIRECTED RNA POLYMERASE I 135 KD 2.00E−45 POLYPEPTIDE (RNA POLYMERASE I SUBUNIT 2) (RPA135) (RNA POLYMERASE I 127 KD SUBUNIT) >gi|2739048 (AF025424) RNA polymerase I 127 kDa subunit [Rattus norvegicus] 6841 4165018 (D89053) Acyl-CoA synthetase 3 [Homo sapiens] 2.00E−53 6842 968973 (U29156) involved in signaling by the epidermal 3.00E−40 growth factor receptor; Method: conceptual translation supplied by author. [Mus musculus] 6843 4519883 (AB017970) dipeptidyl peptidase III 4.00E−50 6844 3327052 (AB014519) KIAA0619 protein [Homo sapiens] 7.00E−30 6845 538413 (L36315) zinc finger protein [Mus musculus] 6.00E−55 6846 1717793 PROTEIN TSG24 (MEIOTIC CHECK POINT 1.00E−50 REGULATOR) >gi|1083553|pir||A55117 tsg24 protein - mouse 6847 3420277 (AF064826) glypican 4 [Homo sapiens] 3.00E−54 6904 4580645 (AF118855) trans-prenyltransferase [Mus musculus] 2.00E−48 6925 3882171 (AB018268) KIAA0725 protein [Homo sapiens] 3.00E−24 6929 4104976 (AF043117) ubiquitin-fusion degradation protein 2 2.00E−41 [Homo sapiens] 6937 3242214 (AJ006778) DRIM protein [Homo sapiens] 4.00E−34 7010 4191810 (AB006532) DNA helicase [Homo sapiens] 5.00E−41 7055 3043714 (AB011167) KIAA0595 protein [Homo sapiens] 5.00E−20 7078 4379097 (Y17999) Dyrkl B protein kinase [Homo sapiens] 3.00E−21 7124 3043712 (AB011166) KIAA0594 protein [Homo sapiens] 2.00E−49 7175 4240227 (AB020676) KIAA0869 protein [Homo sapiens] 4.00E−35 7187 4235226 (AF061025) leucine zipper-EF-hand containing 6.00E−34 transmembrane protein 1 [Homo sapiens] 7230 3426268 (AF044201) neural membrane protein 35; NMP35 1.00E−29 [Rattus norvegicus] 7248 4507367 threonyl-tRNA synthetase SYNTHETASE, 3.00E−26 CYTOPLASMIC (THREONINE--TRNA LIGASE) (THRRS) 6.1.1.3) - human >gi|1464742 (M63180) threonyl-tRNA synthetase [Homo sapiens] 7249 2072294 (U95097) mitotic phosphoprotein 43 [Xenopus laevis] 1.00E−19 7259 543222 glutamine (Q)-rich factor 1, QRF-1 - mouse factor 1, 1.00E−39 QRF-1 [mice, B-cell leukemia, BCL1, Peptide Partial, 84 aa] 7260 3335569 (AF072759) fatty acid transport protein 4; FATP4 7.00E−39 [Mus musculus] 7264 2996194 (AF053232) SIK similar protein [Mus musculus] 1.00E−31 7268 2935597 (AC004262) R29368_2 [Homo sapiens] 6.00E−49 7297 2645205 (U63648) p160 myb-binding protein [Mus musculus] 1.00E−21 7300 1407655 (U58884) SH3P7 [Mus musculus] 8.00E−21 7310 2134381 polybromo 1 protein - chicken 8.00E−29 7315 4505613 PRKC, apoptosis, WT1, regulator par-4 [Homo 6.00E−34 sapiens] 7325 3757892 (AF079765) enhancer of polycomb [Mus musculus] 3.00E−41 7327 2134436 zinc finger protein - chicken (fragment) 4.00E−37 7328 2393722 (U90313) glutathione-S-transferase homolog [Homo 6.00E−34 sapiens] 7330 459002 (U00036) R151.6 gene product [Caenorhabditis 7.00E−10 elegans] 7332 119530 PROTEIN DISULFIDE ISOMERASE-RELATED 3.00E−23 PROTEIN PRECURSOR (ERP72) >gi|87320|pir||A23723 protein disulfide-isomerase (EC 5.3.4.1) ERp72 precursor - human protein [Homo sapiens] 7335 2073541 (L19437) transaldolase [Homo sapiens] >gi|2612879 2.00E−24 7337 984125 (X90857) - 14 [Homo sapiens] 2.00E−23 7341 4106818 (AF083395) phospholipase A2-activating protein 4.00E−36 [Homo sapiens] 7343 4507955 YY1 transcription factor REPRESSOR PROTEIN 4.00E−27 YY1 (YIN AND YANG 1) (YY-1) (DELTA TRANSCRIPTION FACTOR) (NF-E1) >gi|38011|emb|CAA78455| 7346 1698779 (U70372) PAM COOH-terminal interactor protein 2 6.00E−35 [Rattus norvegicus] 7348 4204684 (AF102542) beta-1,6-N-acetylglucosaminyltransferase 9.00E−43 core 2/core 4 beta-1,6-N- acetylglucosaminyltransferase; core 2/4-GnT [Homo sapiens] 7351 2239126 (Y10746) methyl-CpG binding protein [Homo sapiens] 4.00E−16 7355 1747519 (U76759) nuclear protein NIP45 [Mus musculus] 2.00E−29 7356 545790 DARPP-32 = dopamine and cAMP-regulated 1.00E−29 phosphoprotein [human, brain, Peptide, 204 aa] sapiens] 7357 1709689 PEPTIDE METHIONINE SULFOXIDE 1.00E−37 REDUCTASE (PEPTIDE MET(O) REDUCTASE) >gi|1205993 taurus] 7361 2736151 (AF021935) mytonic dystrophy kinase-related Cdc42- 1.00E−41 binding kinase [Rattus norvegicus] 7363 3329392 (AF038961) SL15 protein [Homo sapiens] 8.00E−36 7364 4097712 (U67322) HBV associated factor [Homo sapiens] 7.00E−56 7365 585084 ELONGATION FACTOR G, MITOCHONDRIAL 7.00E−49 PRECURSOR (MEF-G) >gi|543383|pir||S40780 translation elongation factor G, mitochondrial - rat >gi|310102 7366 1438534 (U49057) rA9 [Rattus norvegicus] 3.00E−45 7367 1336628 (U57368) EGF repeat transmembrane protein [Mus 7.00E−47 musculus] 7368 3914802 DNA-DIRECTED RNA POLYMERASE I LARGEST 1.00E−37 SUBUNIT (RNA POLYMERASE I 194 KD SUBUNIT) (RPA194) 7369 3387977 (AF070598) ABC transporter [Homo sapiens] 5.00E−50 7370 1717793 PROTEIN TSG24 (MEIOTIC CHECK POINT 2.00E−48 REGULATOR) >gi|1083553|pir||A55117 tsg24 protein - mouse 7371 2493735 SKD3 PROTEIN SKD3 [Mus musculus] 7.00E−43 7372 1041038 (D78020) NFI-A4 [Rattus norvegicus] 3.00E−26 7380 4455118 (AF125158) zinc finger DNA binding protein 99 9.00E−41 7418 4049922 (AF072810) transcription factor WSTF [Homo 4.00E−48 sapiens] 7434 4586287 (AB004794) DUF140 [Xenopus laevis] 3.00E−45 7441 3435244 (AF083322) centriole associated protein CEP110 2.00E−40 [Homo sapiens] 7466 3413886 (AB007931) KIAA0462 protein [Homo sapiens] 2.00E−35 7558 3882311 (AB018338) KIAA0795 protein [Homo sapiens] 4.00E−47 7593 4240167 (AB020646) KIAA0839 protein [Homo sapiens] 2.00E−46 7613 4191610 (AF117107) IGF-II mRNA-binding protein 2 [Homo 3.00E−49 sapiens] 7615 3135669 (AF064084) prenylcysteine carboxyl methyltransferase 1.00E−39 7625 3043548 (AB011084) KIAA0512 protein [Homo sapiens] 2.00E−47 7627 3093476 (AF008915) EVI-5 homolog [Homo sapiens] 6.00E−19 7628 3834629 (AF094519) diaphanous-related formin; p134 mDia2 1.00E−32 [Mus musculus] 7629 3193226 (AF068706) gamma2-adaptin [Homo sapiens] 1.00E−46 7630 3851584 (AF092563) chromosome-associated protein-E [Homo 4.00E−48 sapiens] 7631 4101695 (AF006010) progestin induced protein [Homo sapiens] 5.00E−30 7646 3850704 (AJ005273) Kin17 [Homo sapiens] 9.00E−24 7649 4240147 (AB020636) KIAA0829 protein [Homo sapiens] 9.00E−41 7650 2137490 lymphocyte specific helicase - mouse musculus] 5.00E−35 7657 3327052 (AB014519) KIAA0619 protein [Homo sapiens] 1.00E−41 7659 2137494 M-sema F protein precusor - mouse F [mice, neonatal 7.00E−34 brain, Peptide, 834 aa] [Mus sp.] 7660 2137603 nuclear receptor co-repressor N-CoR - mouse 9.00E−41 musculus] >gi|1583865|prf||2121436A thyroid hormone receptor co-repressor [Mus musculus] 7661 2674107 (AF023451) guanine nucleotide-exchange protein [Bos 3.00E−48 taurus] 7683 3659505 (AC005084) similar to mouse mCASK-A; similar to 1.00E−57 e1288039 7745 114762 NUCLEOPHOSMIN (NPM) (NUCLEOLAR 6.00E−35 PHOSPHOPROTEIN B23) (NUMATRIN) (NUCLEOLAR PROTEIN NO38) sapiens] 7747 3327056 (AB014521) KIAA0621 protein [Homo sapiens] 8.00E−40 7784 4545264 (AF118240) peroxisomal biogenesis factor 16 [Homo 2.00E−65 sapiens] 7790 2498864 RRP5 PROTEIN HOMOLOG (KIAA0185) 7.00E−77 hypothetical protein YM9959.11C of S. cerevisiae. [Homo sapiens] 7854 3420277 (AF064826) glypican 4 [Homo sapiens] 4.00E−76 7864 3088575 (AF059531) protein arginine N-methyltransferase 3 7.00E−97 [Homo sapiens] 7867 4050034 (AF098482) transcriptional coactivator p52 [Homo 2.00E−58 sapiens] 7907 4506357 UNKNOWN; PZR >gi|3851145 sapiens] 2.00E−60 7926 3387977 (AF070598) ABC transporter [Homo sapiens] e−113 7932 1709974 60S RIBOSOMAL PROTEIN L10A protein L10a e−111 [Rattus norvegicus] Ribosomal Protein RPL10A) [Homo sapiens] 7934 4507709 tissue specific transplantation antigen P35B 9.00E−90 >gi|1381179 (U58766) FX [Homo sapiens] 7972 1117791 (U18297) MST1 [Homo sapiens] 4E−85 7973 4507015 copper transporter 1 3.00E−72 7993 4503301 2,4-dienoyl CoA reductase REDUCTASE, 6E−94 MITOCHONDRIAL PRECURSOR (2,4-DIENOYL- COA REDUCTASE (NADPH)) (4-ENOYL-COA REDUCTASE (NADPH)) precursor, mitochondrial - human >gi|602703 (L26050) 2,4-dienoyl-CoA reductase [Homo sapiens] >gi|2673979 precursor [Homo sapiens] >gi|4126313 (AF049895) 2,4-dienoyl- CoA reductase [Homo sapiens] 7997 126743 MICROTUBULE-ASSOCIATED PROTEIN 4 human 6E−84 >gi|187383 (M64571) microtubule-associated protein 4 [Homo sapiens] 8010 4505987 PTPRF interacting protein, binding protein 1 (liprin 4E−89 beta 1) >gi|3309539 (AF034802) liprin-beta1 [Homo sapiens] 8016 3043644 (AB011132) KIAA0560 protein [Homo sapiens] e−108 8040 3413892 (AB007934) KIAA0465 protein [Homo sapiens] 7.00E−87 8052 4185796 (AF103796) placenta-specific ATP-binding cassette 2E−68 transporter [Homo sapiens] 8069 4507145 UNKNOWN >gi|3873216 (AF065485) sorting nexin 4 1.00E−73 [Homo sapiens] 8104 1083566 zinc finger protein/transactivator Zfp-38 - mouse 2E−64 >gi|55477|emb|CAA45280|(X63747) Zfp-38 [Mus musculus] 8114 1806134 (Z67747) zinc finger protein [Mus musculus] 7.00E−78 8128 730451 60S RIBOSOMAL PROTEIN L13A (23 KD HIGHLY 4.00E−87 BASIC PROTEIN) >gi|345897|pir||S29539 basic protein, 23 K - human >gi|23691|emb|CAA40254| (X56932) 23 kD highly basic protein [Homo sapiens] 8381 4102967 (AF023142) pre-mRNA splicing SR protein rA4 1.00E−33 [Homo sapiens] 8413 3108093 (AF061258) LIM protein [Homo sapiens] 6.00E−82 8414 3170887 (AF061555) ubiquitin-protein ligase E3-alpha [Mus e−104 musculus] 8420 1552350 (Y08135) acid sphingomyelinase-like 6.00E−91 phosphodiesterase [Mus musculus] 8461 1552350 (Y08135) acid sphingomyelinase-like e−106 phosphodiesterase [Mus musculus] 8462 3242214 (AJ006778) DRIM protein [Homo sapiens] e−114 8483 4514653 (AB024057) vascular Rab-GAP/TBC-containing e−121 protein [Homo sapiens] 8537 2443367 (AB005216) Nck, Ash and phospholipase C gamma- e−120 binding protein NAP4 [Homo sapiens] 8571 119110 EBNA-1 NUCLEAR PROTEIN herpesvirus 4 (strain 2.00E−38 B95-8) >gi|1334880|emb|CAA24816.1|gene. [Human herpesvirus 4] 8575 121640 GLYCINE-RICH CELL WALL STRUCTURAL 8.00E−31 PROTEIN PRECURSOR >gi|72320|pir||KNMU glycine-rich cell wall protein precursor - Arabidopsis thaliana 8591 1362077 glycin-rich protein - cowpea (fragment) 2E−40 8615 121640 GLYCINE-RICH CELL WALL STRUCTURAL 9.00E−27 PROTEIN PRECURSOR >gi|72320|pir||KNMU glycine-rich cell wall protein precursor - Arabidopsis thaliana 8642 2674107 (AF023451) guanine nucleotide-exchange protein [Bos 5E−89 taurus] 8644 3717978 (Y12431) 5S ribosomal protein [Mus musculus] 5E−94 8652 4191610 (AF117107) IGF-II mRNA-binding protein 2 [Homo e−111 sapiens] 8674 2119281 CHO1 antigen - Chinese hamster e−101 8675 3435244 (AF083322) centriole associated protein CEP110 2E−70 [Homo sapiens] 8687 1843434 (D88687) KM-102-derived reductase-like factor 4.00E−91 [Homo sapiens] 8700 3834629 (AF094519) diaphanous-related formin; p134 mDia2 1E−49 [Mus musculus]

Example 29 Members of Protein Families

SEQ ID NOS: 7662-8706 were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein family (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 42A, inserted prior to claims). Table 42A provides the SEQ ID NO: of the query sequence, a brief description of the profile hit, the position of the query sequence within the individual sequence (indicated as “start” and “stop”), and the orientation (Direction) of the query sequence with respect to the individual sequence, where forward (for) indicates that the alignment is in the same direction (left to right) as the sequence provided in the Sequence Listing and reverse (rev) indicates that the alignment is with a sequence complementary to the sequence provided in the Sequence Listing.

TABLE 42A Profile Hits SEQ ID NO: Description Start Stop Dir 8063 14_3_3 proteins 166 845 for 8462 3′5′-cyclic nucleotide phosphodiesterases 64 573 for 7675 4 transmembrane integral membrane 300 924 rev proteins 8074 4 transmembrane integral membrane 340 941 rev proteins 7748 7 transmembrane receptor (rhodopsin 109 647 rev family) 8023 7 transmembrane receptor (rhodopsin 84 947 rev family) 8164 7 transmembrane receptor (rhodopsin 305 975 for family) 7694 7 transmembrane receptor (Secretin 50 1269 for family) 7815 7 transmembrane receptor (Secretin 63 1160 rev family) 8007 7 transmembrane receptor (Secretin 38 869 rev family) 8023 7 transmembrane receptor (Secretin 237 930 rev family) 8164 7 transmembrane receptor (Secretin 188 975 for family) 8437 7 transmembrane receptor (Secretin 377 1524 rev family) 7767 ATPases Associated with Various 136 718 for Cellular Activities 7768 ATPases Associated with Various 271 765 for Cellular Activities 7784 ATPases Associated with Various 206 709 rev Cellular Activities 7892 ATPases Associated with Various 139 783 for Cellular Activities 7926 ATPases Associated with Various 265 713 for Cellular Activities 7968 ATPases Associated with Various 152 616 rev Cellular Activities 8009 ATPases Associated with Various 12 510 for Cellular Activities 8018 ATPases Associated with Various 125 658 for Cellular Activities 8060 ATPases Associated with Various 97 752 for Cellular Activities 8093 ATPases Associated with Various 185 664 for Cellular Activities 8128 ATPases Associated with Various 69 485 for Cellular Activities 8266 ATPases Associated with Various 73 550 for Cellular Activities 8273 ATPases Associated with Various 340 928 for Cellular Activities 8386 ATPases Associated with Various 872 1390 rev Cellular Activities 8439 ATPases Associated with Various 122 635 for Cellular Activities 8454 ATPases Associated with Various 84 492 rev Cellular Activities 8486 ATPases Associated with Various 31 434 rev Cellular Activities 8510 ATPases Associated with Various 953 1358 rev Cellular Activities 8557 ATPases Associated with Various 192 690 rev Cellular Activities 8572 ATPases Associated with Various 51 593 for Cellular Activities 8578 ATPases Associated with Various 135 615 rev Cellular Activities 8674 ATPases Associated with Various 0 673 for Cellular Activities 7719 Basic region plus leucine zipper 81 277 for transcription factors 7811 C2 domain (prot. kinase C like) 403 582 for 8522 C2 domain (prot. kinase C like) 493 637 for 8334 Cysteine proteases 359 984 rev 7726 DEAD and DEAH box helicases 34 690 rev 7961 DEAD and DEAH box helicases 43 753 for 8613 DEAD and DEAH box helicases 426 719 for 7810 Dual specificity phosphatase, catalytic 365 696 rev domain 7824 Dual specificity phosphatase, catalytic 243 597 for domain 8183 Dual specificity phosphatase, catalytic 786 1566 for domain 7691 EF-hand 556 630 for 7767 Eukaryotic aspartyl proteases 116 763 for 7874 Eukaryotic aspartyl proteases 92 1008 rev 7999 Eukaryotic aspartyl proteases 73 603 rev 8041 Eukaryotic aspartyl proteases 147 694 rev 8059 Eukaryotic aspartyl proteases 38 740 rev 8087 Eukaryotic aspartyl proteases 404 1113 rev 8226 Eukaryotic aspartyl proteases 237 829 rev 8234 Eukaryotic aspartyl proteases 117 729 rev 8289 Eukaryotic aspartyl proteases 217 1397 rev 8386 Eukaryotic aspartyl proteases 413 1366 rev 8387 Eukaryotic aspartyl proteases 8 710 rev 8444 Eukaryotic aspartyl proteases 291 1146 rev 8526 Eukaryotic aspartyl proteases 216 1158 rev 8592 Eukaryotic aspartyl proteases 228 659 for 8619 Eukaryotic aspartyl proteases 276 1291 rev 8685 Eukaryotic aspartyl proteases 525 1431 for 8064 Fibronectin type II domain 455 565 rev 7875 G-protein alpha subunit 24 583 rev 7717 Helicases conserved C-terminal domain 160 309 for 7748 Helicases conserved C-terminal domain 363 560 rev 8288 Helix-loop-helix DNA binding domain 224 382 for 8277 kinase domain of tors 474 713 for 7921 mkk like kinases 17 626 rev 7972 mkk like kinases 35 719 for 8135 mkk like kinases 114 527 for 8622 mkk like kinases 9 463 for 7878 Neurotransmitter-gated ion-channel 267 1411 for 8018 Neurotransmitter-gated ion-channel 367 1168 for 8164 Neurotransmitter-gated ion-channel 222 1024 for 8198 Neurotransmitter-gated ion-channel 352 1273 for 8250 Neurotransmitter-gated ion-channel 377 1159 for 8634 Neurotransmitter-gated ion-channel 112 1120 for 7717 protein kinase 153 743 for 7726 protein kinase 123 904 for 7801 protein kinase 471 1072 for 7802 protein kinase 190 609 for 7806 protein kinase 235 641 for 7840 protein kinase 8 711 rev 7863 protein kinase 90 537 for 7872 protein kinase 200 524 rev 7878 protein kinase 706 1331 for 7918 protein kinase 24 666 for 7921 protein kinase 56 593 rev 7940 protein kinase 263 824 for 7946 protein kinase 217 779 for 7972 protein kinase 290 711 for 8073 protein kinase 38 776 for 8147 protein kinase 14 657 for 8208 protein kinase 202 644 rev 8265 protein kinase 1 656 for 8301 protein kinase 57 689 for 8338 protein kinase 33 646 for 8387 protein kinase 630 1148 rev 8550 protein kinase 49 761 rev 8622 protein kinase 0 463 for 8654 protein kinase 77 590 for 7815 Protein Tyrosine Phosphatase 82 482 rev 7865 Protein Tyrosine Phosphatase 71 461 rev 8158 Protein Tyrosine Phosphatase 270 704 for 8293 Protein Tyrosine Phosphatase 359 851 for 8371 Protein Tyrosine Phosphatase 56 680 for 7946 RNA recognition motif. (aka RRM, RBD, 165 365 for or RNP domain) 8290 RNA recognition motif. (aka RRM, RBD, 37 174 for or RNP domain) 8537 SH2 Domain 201 362 for 7714 Thioredoxins 253 554 for 7675 Trypsin 252 1007 rev 8386 Trypsin 350 1164 rev 8437 Trypsin 447 1211 rev 8517 Trypsin 14 765 rev 8526 Trypsin 700 1556 rev 8534 Trypsin 47 670 rev 8377 WD domain, G-beta repeats 70 161 for 7675 wnt family of developmental signaling 282 1017 rev proteins 7749 wnt family of developmental signaling 154 978 rev proteins 7874 wnt family of developmental signaling 38 858 rev proteins 7922 wnt family of developmental signaling 574 1318 rev proteins 7971 wnt family of developmental signaling 578 1313 rev proteins 8000 wnt family of developmental signaling 205 1068 rev proteins 8088 wnt family of developmental signaling 2 824 rev proteins 8100 wnt family of developmental signaling 621 1420 rev proteins 8225 wnt family of developmental signaling 394 1343 rev proteins 8241 wnt family of developmental signaling 162 1027 rev proteins 8300 wnt family of developmental signaling 274 1405 rev proteins 8334 wnt family of developmental signaling 560 1195 rev proteins 8386 wnt family of developmental signaling 250 1273 rev proteins 8387 wnt family of developmental signaling 523 1409 rev proteins 8390 wnt family of developmental signaling 297 1237 rev proteins 8437 wnt family of developmental signaling 51 1002 rev proteins 8439 wnt family of developmental signaling 28 1180 rev proteins 8444 wnt family of developmental signaling 638 1614 rev proteins 8469 wnt family of developmental signaling 30 1078 rev proteins 8505 wnt family of developmental signaling 4 1074 rev proteins 8506 wnt family of developmental signaling 208 1107 rev proteins 8510 wnt family of developmental signaling 242 1068 rev proteins 8517 wnt family of developmental signaling 159 1057 rev proteins 8526 wnt family of developmental signaling 844 1691 rev proteins 8532 wnt family of developmental signaling 107 784 rev proteins 8534 wnt family of developmental signaling 127 1226 rev proteins 8559 wnt family of developmental signaling 5 704 rev proteins 8569 wnt family of developmental signaling 328 1193 rev proteins 8607 wnt family of developmental signaling 341 1222 rev proteins 8619 wnt family of developmental signaling 820 1617 rev proteins 8624 wnt family of developmental signaling 461 1283 rev proteins 7831 Zinc finger, C2H2 type 495 557 for 8038 Zinc finger, C2H2 type 500 562 for 8114 Zinc finger, C2H2 type 279 341 for 8350 Zinc finger, C2H2 type 148 210 for 8611 Zinc finger, C2H2 type 422 484 for

TABLE 42B Profile Hits for Contigs SEQ ID NO: Description Start Stop Dir 8737 ATPases Associated with Various Cellular 118 661 for Activities 8751 ATPases Associated with Various Cellular 135 536 for Activities 8781 ATPases Associated with Various Cellular 142 574 for Activities 8744 DEAD and DEAH box helicases 66 931 rev 8782 Helicases conserved C-terminal domain 51 242 for 8757 Neurotransmitter-gated ion-channel 169 738 rev 8736 Protein phosphatase 2A regulatory subunit 275 1510 for PR55 8751 Protein phosphatase 2A regulatory subunit 55 1087 for PR55 8766 Protein phosphatase 2A regulatory subunit 13 1183 for PR55 8780 Protein phosphatase 2A regulatory subunit 511 1861 rev PR55 8775 Protein Tyrosine Phosphatase 292 768 for 8764 Thioredoxins 182 475 for

Some polynucleotides exhibited multiple profile hits where the query sequence contains overlapping profile regions, and/or where the sequence contains two different functional domains. Each of the profile hits of Table 42A are described in more detail below. The acronyms for the profiles (provided in parentheses) are those used to identify the profile in the Pfam and Prosite databases. The Pfam database can be accessed through many URLS. The Prosite database can be accessed at the Expasy website. The public information available on the Pfam and Prosite databases regarding the various profiles, including but not limited to the activities, function, and consensus sequences of various proteins families and protein domains, is incorporated herein by reference.

14-3-3 Family (14_(—)3_(—)3). Some SEQ ID NOS corresponds to a sequence encoding a 14-3-3 protein family member. The 14-3-3 protein family includes a group of closely related acidic homodimeric proteins of about 30 kD first identified as very abundant in mammalian brain tissues and located preferentially in neurons (Aitken et al. Trends Biochem. Sci. (1995) 20:95-97; Morrison Science (1994) 266:56-57; and Xiao et al. Nature (1995) 376:188-191). The 14-3-3 proteins have multiple biological activities, including a key role in signal transduction pathways and the cell cycle. 14-3-3 proteins interact with kinases (e.g., PKC or Raf-1), and can also function as protein-kinase dependent activators of tyrosine and tryptophan hydroxylases. The 14-3-3 protein sequences are extremely well conserved, and include two highly conserved regions: the first is a peptide of 11 residues located in the N-terminal section; the second, a 20 amino acid region located in the C-terminal section.

3′5′-Cyclin Nucleotide Phosphodiesterases (PDEase). Some SEQ ID NOS represent a polynucleotide encoding a novel 3′5′-cyclic nucleotide phosphodiesterase. PDEases catalyze the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5′ monophosphates (Charbonneau et al, Proc. Natl. Acad. Sci. U.S.A. (1986) 83:9308). There are at least seven different subfamilies of PDEases (Beavo et al., Trends Pharmacol. Sci. (1990) 11:150; see internet web site at weber.u.washington.edu/.about.pde/: 1) Type 1, calmodulin/calcium-dependent PDEases; 2) Type 2, cGMP-stimulated PDEases; 3) Type 3, cGMP-inhibited PDEases; 4) Type 4, cAMP-specific PDEases; 5) Type 5, cGMP-specific PDEases; 6) Type 6, rhodopsin-sensitive cGMP-specific PDEases; and 7) Type 7, High affinity cAMP-specific PDEases. All PDEase forms share a conserved domain of about 270 residues.

Four Transmembrane Integral Membrane Proteins (transmembrane4). Some SEQ ID NOS correspond to a sequence encoding a member of the four transmembrane segments integral membrane protein family (tm4 family). The tm4 family of proteins includes a number of evolutionarily-related eukaryotic cell surface antigens (Levy et al., J. Biol. Chem., (1991) 266:14597; Tomlinson et al., Eur. J. Immunol. (1993) 23:136; Barclay et al. The leucocyte antigen factbooks. (1993) Academic Press, London/San Diego). The tm4 family members are type III membrane proteins, which are integral membrane proteins containing an N-terminal membrane-anchoring domain that functions both as a translocation signal and as a membrane anchor. The family members also contain three additional transmembrane regions, at least seven conserved cysteines residues, and are of approximately the same size (218 to 284 residues). The consensus pattern spans a conserved region including two cysteines located in a short cytoplasmic loop between two transmembrane domains:

Seven Transmembrane Integral Membrane Proteins—Rhodopsin Family (7tm_(—)1). Some SEQ ID NOS correspond to a sequence encoding a member of the seven transmembrane (7tm) receptor rhodopsin family. G-protein coupled receptors of the (7tm) rhodopsin family include hormones, neurotransmitters, and light receptors that transduce extracellular signals by interaction with guanine nucleotide-binding (G) proteins (Strosberg Eur. J. Biochem. (1991) 196:1, Kerlavage Curr. Opin. Struct. Biol. (1991) 1:394, Probst, et al., DNA Cell Biol. (1992) 11:1, Savarese, et al., Biochem. J. (1992) 283:1)

Seven Transmembrane Integral Membrane Proteins—Secretin Family (7tm_(—)2). Some SEQ ID NOS correspond to a sequence encoding a member of the seven transmembrane receptor (7tm) secretin family (Jueppner et al. Science (1991) 254:1024; Hamann et al. Genomics (1996) 32:144). The N-terminal extracellular domain of these receptors contains five conserved cysteines residues involved in disulfide bonds, with a consensus pattern in the region that spans the first three cysteines. One of the most highly conserved regions spans the C-terminal part of the last transmembrane region and the beginning of the adjacent intracellular region and is used as a second signature pattern.

ATPases Associated with Various Cellular Activities (ATPases). Several of the polynucleotides of the invention correspond to a sequence that encodes a member of a family of ATPases Associated with diverse cellular Activities (AAA). The AAA protein family is composed of a large number of ATPases that share a conserved region of about 220 amino acids containing an ATP-binding site (Froehlich et al., J. Cell Biol. (1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieri et al., BioEssays (1995) 17:639). The AAA domain, which can be present in one or two copies, acts as an ATP-dependent protein clamp (Confalonieri et al. (1995) BioEssays 17:639) and contains a highly conserved region located in the central part of the domain.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP). One SEQ ID NO represents a polynucleotide encoding a novel member of the family of basic region plus leucine zipper transcription factors. The bZIP superfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcription factors encompasses proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper required for dimerization.

C2 domain (C2). Some SEQ ID NOS correspond to a sequence encoding a C2 domain, which is involved in calcium-dependent phospholipid binding (Davletov J. Biol. Chem. (1993) 268:26386-26390) or, in proteins that do not bind calcium, the domain may facilitate binding to inositol-1,3,4,5-tetraphosphate (Fukuda et al. J. Biol. Chem. (1994) 269:29206-29211; Sutton et al. Cell (1995) 80:929-938).

Cysteine proteases (Cys-protease). One SEQ ID NO represents a polynucleotide encoding a protein having a eukaryotic thiol (cysteine) protease active site. Cysteine proteases (Dufour Biochimie (1988) 70:1335) are a family of proteolytic enzymes that contain an active site cysteine. Catalysis proceeds through a thioester intermediate and is facilitated by a nearby histidine side chain; an asparagine completes the essential catalytic triad.

DEAD and DEAR box families ATP-dependent helicases (Dead_box_helic). Some SEQ ID NOS represent polynucleotides encoding a novel member of the DEAD and DEAR box families (Schmid et al., Mol. Microbiol. (1992) 6:283; Linder et al., Nature (1989) 337:121; Wassarman, et al., Nature (1991) 349:463). All members of these families are involved in ATP-dependent, nucleic-acid unwinding. All DEAD box family members share a number of conserved sequence motifs, some of which are specific to the DEAD family, with others shared by other ATP-binding proteins or by proteins belonging to the helicases ‘superfamily’ (Hodgman Nature (1988) 333:22 and Nature (1988) 333:578 (Errata); see worldwide web site at expasy.ch/www/linder/HELICASES_TEXT.html). One of these motifs, called the ‘D-E-A-D-box’, represents a special version of the B motif of ATP-binding proteins. Proteins that have His instead of the second Asp and are ‘D-E-A-H-box’ proteins (Wassarman et al., Nature (1991) 349:463; Harosh, et al., Nucleic Acids Res. (1991) 19:6331; Koonin, et al., J. Gen. Virol. (1992) 73:989; see worldwide web site at expasy.ch/www/linder/HELICASES_TEXT.html).

Dual specificity phosphatase (DSPc). Dual specificity phosphatases (DSPs) are Ser/Thr and Tyr protein phosphatases that comprise a tertiary fold highly similar to that of tyrosine-specific phosphatases, except for a “recognition” region connecting helix alpha1 to strand beta1. This tertiary fold may determine differences in substrate specific between VH-1 related dual specificity phosphatase (VHR), the protein tyrosine phosphatases (PTPs), and other DSPs. Phosphatases are important in the control of cell growth, proliferation, differentiation and transformation.

EF Hand (EFhand). One SEQ ID NO corresponds to a polynucleotide encoding a member of the EF-hand protein family, a calcium binding domain shared by many calcium-binding proteins belonging to the same evolutionary family (Kawasaki et al., Protein. Prof. (1995) 2:305-490). The domain is a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain, with a calcium ion coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).

Eukaryotic Aspartyl Proteases (asp). Several of the polynucleotides of the invention correspond to a sequence encoding a novel eukaryotic aspartyl protease. Aspartyl proteases, known as acid proteases, (EC 3.4.23.-) are a widely distributed family of proteolytic enzymes (Foltmann., Essays Biochem. (1981) 17:52; Davies, Annu. Rev. Biophys. Chem. (1990) 19:189; Rao, et al., Biochemistry (1991) 30:4663) known to exist in vertebrates, fungi, plants, retroviruses and some plant viruses. Aspartate proteases of eukaryotes are monomeric enzymes which consist of two domains. Each domain contains an active site centered on a catalytic aspartyl residue.

Fibronectin Type II collagen-binding domain (FntypeII). One SEQ ID NO corresponds to a polynucleotide encoding a polypeptide having a type II fibronectin collagen binding domain. Fibronectin is a plasma protein that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. The major part of the sequence of fibronectin consists of the repetition of three types of domains, called type I, II, and III (Skorstengaardet al., Eur. J. Biochem. (1986) 161:441). The type II domain, which is duplicated in fibronectin, is approximately forty residues long, contains four conserved cysteines involved in disulfide bonds and is part of the collagen-binding region of fibronectin.

G-Protein Alpha Subunit (G-alpha). One SEQ ID NO corresponds to a gene encoding a member of the G-protein alpha subunit family. G-proteins are a family of membrane-associated proteins that couple extracellularly-activated integral-membrane receptors to intracellular effectors, such as ion channels and enzymes that vary the concentration of second messenger molecules. G-proteins are composed of 3 subunits (alpha, beta and gamma) which, in the resting state, associate as a trimer at the inner face of the plasma membrane. The alpha subunit, which binds GTP and exhibits GTPase activity, is about 350-400 amino acids in length with a molecular weight in the range of 40-45 kDa. Seventeen distinct types of alpha subunit have been identified in mammals, and fall into 4 main groups on the basis of both sequence similarity and function: alpha-s, alpha-q, alpha-i and alpha-12 (Simon et al., Science (1993) 252:802). They are often N-terminally acylated, usually with myristate and/or palmitoylate, and these fatty acid modifications can be important for membrane association and high-affinity interactions with other proteins.

Helicases conserved C-terminal domain (helicase_C). Some SEQ ID NOS represent polynucleotides encoding novel members of the DEAD/H helicase family. The DEAD and DEAH families are described above.

Helix-Loop-Helix (HLH) DNA Binding Domain (HLH). One SEQ ID NO corresponds to a sequence encoding an HLH domain. The HLH domain, which normally spans about 40 to 50 amino acids, is present in a number of eukaryotic transcription factors. The HLH domain is formed of two amphipathic helices joined by a variable length linker region that forms a loop that mediates protein dimerization (Murre et al. Cell (1989) 56:777-783). Basic HLH proteins (bHLH), which have an extra basic region of about 15 amino acid residues adjacent the HLH domain and specifically bind to DNA, include two groups: class A (ubiquitous) and class B (tissue-specific). bHLH family members bind variations of the E-box motif (CANNTG). The homo- or heterodimerization mediated by the HLH domain is independent of, but necessary for DNA binding, as two basic regions are required for DNA binding activity. The HLH proteins lacking the basic domain function as negative regulators since they form heterodimers, but fail to bind DNA.

Kinase Domain of Tors. The TOR profile is directed towards a lipid kinase protein family. This family is composed of large proteins with a lipid and protein kinase domain and characterized through their sensitivity to rapamycin (an antifungal compound). TOR proteins are involved in signal transduction downstream of PI3 kinase and many other signals. TOR (also called FRAP, RAFT) plays a role in regulating protein synthesis and cell growth, and in yeast controls translation initiation and early G1 progression. See, e.g., Barbet et al. Mol Biol Cell. (1996) 7(1):25-42; Helliwell et al. Genetics (1998) 148:99-112.

MAP kinase kinase (mkk). Some SEQ ID NOS represent members of the MAP kinase kinase (mkk) family. MAP kinases (MAPK) are involved in signal transduction, and are important in cell cycle and cell growth controls. The MAP kinase kinases (MAPKK) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKKs are essential transducers through which signals must pass before reaching the nucleus. For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishida et al., Trends Biochem Sci (1993) 18:128-31; Ruderman Curr Opin Cell Biol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55; Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal (1996) 8:533-44.

Neurotransmitter-Gated Ion-Channel (neur_chan). Several of the sequences correspond to a sequence encoding a neurotransmitter-gated ion channel. Neurotransmitter-gated ion-channels, which provide the molecular basis for rapid signal transmission at chemical synapses, are post-synaptic oligomeric transmembrane complexes that transiently form a ionic channel upon the binding of a specific neurotransmitter. Five types of neurotransmitter-gated receptors are known: 1) nicotinic acetylcholine receptor (AchR); 2) glycine receptor; 3) gamma-aminobutyric-acid (GABA) receptor; 4) serotonin 5HT3 receptor; and 5) glutamate receptor. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related, and are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions that form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence.

Protein Kinase (protkinase). Several sequences represent polynucleotides encoding protein kinases, which catalyze phosphorylation of proteins in a variety of pathways, and are implicated in cancer. Eukaryotic protein kinases (Hanks, et al., FASEB J. (1995) 9:576; Hunter, Meth. Enzymol. (1991) 200:3; Hanks, et al., Meth. Enzymol. (1991) 200:38; Hanks, Curr. Opin. Struct. Biol. (1991) 1:369; Hanks et al., Science (1988) 241:42) belong to a very extensive family of proteins that share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. The first region, located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. The second region, located in the central part of the catalytic domain, contains a conserved an aspartic acid residue that is important for the catalytic activity of the enzyme (Knighton, et al., Science (1991) 253:407).

The protein kinase profile includes two signature patterns for this second region: one specific for serine/threonine kinases and the other for tyrosine kinases. A third profile is based on the alignment in (Hanks, et al., FASEB J. (1995) 9:576) and covers the entire catalytic domain.

Protein Tyrosine Phosphatase (Y_phosphatase) (PTPase). Some SEQ ID NOS represent polynucleotides encoding a tyrosine-specific protein phosphatase, a kinase that catalyzes the removal of a phosphate groups attached to a tyrosine residue (EC 3.1.3.48) (PTPase) (Fischer et al., Science (1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463; Trowbridge Biol. Chem. (1991) 266:23517; Tonks et al., Trends Biochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013). PTPases are important in the control of cell growth, proliferation, differentiation and transformation. Multiple forms of PTPase have been characterized and can be classified into two categories: soluble PTPases and transmembrane receptor proteins that contain PTPase domain(s). Structurally, all known receptor PTPases are made up of a variable length extracellular domain, followed by a transmembrane region and a C-terminal catalytic cytoplasmic domain. PTPase domains consist of about 300 amino acids. Two conserved cysteines are absolutely required for activity, with a number of other conserved residues in the immediate vicinity also important for activity.

RNA Recognition Motif (rrm). Some SEQ ID NOS correspond to sequence encoding an RNA recognition motif, also known as an RRM, RBD, or RNP domain. This domain, which is about 90 amino acids long, is contained in eukaryotic proteins that bind single-stranded RNA (Bandziulis et al. Genes Dev. (1989) 3:431-437; Dreyfuss et al. Trends Biochem. Sci. (1988) 13:86-91). Two regions within the RNA-binding domain are highly conserved: the first is a hydrophobic segment of six residues (which is called the RNP-2 motif), the second is an octapeptide motif (which is called RNP-1 or RNP-CS).

SH2 Domain (SH2). One SEQ ID NO corresponds to a sequence encoding an SH2 domain. The Src homology 2 (SH2) domain includes an approximately 100 amino acid residue domain, which is conserved in the oncoproteins Src and Fps, as well as in many other intracellular signal-transducing proteins (Sadowski et al. Mol. Cell. Biol. (1986) 6:4396-4408; Russel et al. FEBS Lett. (1992) 304:15-20). SH2 domains function as regulatory modules of intracellular signaling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific and strictly phosphorylation-dependent manner. The SH2 domain has a conserved 3D structure consisting of two alpha helices and six to seven beta-strands. The core of the domain is formed by a continuous beta-meander composed of two connected beta-sheets (Kuriyan et al. Curr. Opin. Struct. Biol. (1993) 3:828-837).

Thioredoxin family active site (Thioredox). One SEQ ID NO represents a polynucleotide encoding a protein of the thioredoxin family. Thioredoxins are small proteins of approximately one hundred amino acid residues that participate in various redox reactions via the reversible oxidation of an active center disulfide bond (Holmgren, Annu. Rev. Biochem. (1985) 54:237; Gleason, et al., FEMS Microbiol. Rev. (1988) 54:271; Holmgren A. J. Biol. Chem. (1989) 264:13963; Eklund, et al. Proteins (1991) 11:13). Thioredoxins exist in either reduced or oxidized forms where the two cysteine residues are linked in an intramolecular disulfide bond. The sequence around the redox-active disulfide bond is well conserved.

Trypsin (trypsin). Some SEQ ID NOS correspond to novel serine proteases of the trypsin family. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved (Brenner Nature (1988) 334:528). All sequences known to belong to this family are detected by the above consensus sequences, except for 18 different proteases which have lost the first conserved glycine. If a protein includes both the serine and the histidine active site signatures, the probability of it being a trypsin family serine protease is 100%.

WD Domain G-Beta Repeats (WD_domain). One SEQ ID NO represents a member of the WD domain/G-beta repeat family. Beta-transducin (G-beta) is one of the three subunits (alpha, beta, and gamma) of the guanine nucleotide-binding proteins (G proteins) which act as intermediaries in the transduction of signals generated by transmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds to and hydrolyzes GTP; the beta and gamma subunits are required for the replacement of GDP by GTP as well as for membrane anchoring and receptor recognition. In higher eukaryotes, G-beta exists as a small multigene family of highly conserved proteins of about 340 amino acid residues. Structurally, G-beta has eight tandem repeats of about 40 residues, each containing a central Trp-Asp motif (this type of repeat is sometimes called a WD-40 repeat).

wnt Family of Developmental Signaling Proteins (Wnt_dev_sign). Several of the sequences correspond to novel members of the wnt family of developmental signaling proteins. Wnt-1 (previously known as int-1), the seminal member of this family, (Nusse, Trends Genet. (1988) 4:291) plays a role in intercellular communication and is important in central nervous system development. All wnt family proteins share the following features characteristic of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines that may be involved in disulfide bonds. Wnt proteins generally adhere to the plasma membrane of secreting cells and are therefore likely to signal over only few cell diameters.

Zinc Finger, C2H2 Type (Zincfing_C2H2). Some SEQ ID NOS correspond to polynucleotides encoding members of the C2H2 type zinc finger protein family, which contain zinc finger domains that facilitate nucleic acid binding (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99). In addition to the conserved zinc ligand residues, a number of other positions are also important for the structural integrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved position, which is generally an aromatic or aliphatic residue, is located four residues after the second cysteine.

Example 30 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 43 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 43 Description of cDNA Libraries Number of Library Clones in (lib #) Description Cluster 1 Km12 L4 307133 Human Colon Cell Line, High Metastatic Potential (derived from Km12C); “High Met Colon” 2 Km12C 284755 Human Colon Cell Line, Low Metastatic Potential; “Low Met Colon” 3 MDA-MB-231 326937 Human Breast Cancer Cell Line, High Metastatic Potential; micro- metastases in lung; “High Met Breast” 4 MCF7 318979 Human Breast Cancer Cell, Non Metastatic; “Low Met Breast” 8 MV-522 223620 Human Lung Cancer Cell Line, High Metastatic Potential; “High Met Lung” 9 UCP-3 312503 Human Lung Cancer Cell Line, Low Metastatic Potential; “Low Met Lung” 12 Human microvascular endothelial cells (HMEC) - Untreated 41938 PCR (OligodT) cDNA library; “HMEC” 13 Human microvascular endothelial cells (HMEC) - Basic fibroblast 42100 growth factor (bFGF) treated PCR (OligodT) cDNA library; “HMEC-bFGF” 14 Human microvascular endothelial cells (HMEC) - Vascular 42825 endothelial growth factor (VEGF) treated PCR (OligodT) cDNA library; “HMEC-VEGF” 15 Normal Colon - UC#2 Patient 282722 PCR (OligodT) cDNA library; “Normal Colon Tissue” 16 Colon Tumor - UC#2 Patient 298831 PCR (OligodT) cDNA library; “Normal Colon Tumor Tissue” 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467 PCR (OligodT) cDNA library; “High Met Colon Tissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT) cDNA library; “Normal Colon Tissue” 19 Colon Tumor - UC#3 Patient 41388 PCR (OligodT) cDNA library; “Colon Tumor Tissue” 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 PCR (OligodT) cDNA library; “High Met Colon Tissue” 21 GRRpz 164801 Human Prostate Cell Line; “Normal Prostate” 22 Woca 162088 Human Prostate Cancer Cell Line; “Prostate Cancer”

The KM12L4, KM12C, and MDA-MB-231 cell lines are described above. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cell lines were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974).

Examples 31-38 Differential Expression of Polynucleotides of the Invention

A number of polynucleotide sequences have been identified that are differentially expressed between, for example, cells derived from high metastatic potential cancer tissue and low metastatic cancer cells, and between cells derived from high metastatic potential cancer tissue and normal tissue. Evaluation of the levels of expression of the genes corresponding to these sequences can be valuable in diagnosis, prognosis, and/or treatment (e.g., to facilitate rationale design of therapy, monitoring during and after therapy, etc.). Moreover, the genes corresponding to differentially expressed sequences described herein can be therapeutic targets due to their involvement in regulation (e.g., inhibition or promotion) of development of, for example, the metastatic phenotype. For example, sequences that correspond to genes that are increased in expression in high metastatic potential cells relative to normal or non-metastatic tumor cells may encode genes or regulatory sequences involved in processes such as angiogenesis, differentiation, cell replication, and metastasis.

Detection of the relative expression levels of differentially expressed polynucleotides described herein can provide valuable information to guide the clinician in the choice of therapy. For example, a patient sample exhibiting an expression level of one or more of these polynucleotides that corresponds to a gene that is increased in expression in metastatic or high metastatic potential cells may warrant more aggressive treatment for the patient. In contrast, detection of expression levels of a polynucleotide sequence that corresponds to expression levels associated with that of low metastatic potential cells may warrant a more positive prognosis than the gross pathology would suggest.

A number of polynucleotide sequences of the present invention are differentially expressed between human microvascular endothelial cells (HMEC) that have been treated with growth factors relative to untreated HMEC. Sequences that are differentially expressed between growth factor-treated HMEC and untreated HMEC can represent sequences encoding gene products involved in angiogenesis, metastasis (cell migration), and other development and oncogenic processes. For example, sequences that are more highly expressed in HMEC treated with growth factors (such as bFGF or VEGF) relative to untreated HMEC can serve as markers of cancer cells of higher metastatic potential. Detection of expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The differential expression of the polynucleotides described herein can thus be used as, for example, diagnostic markers, prognostic markers, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers. The following examples provide relative expression levels of polynucleotides from specified cell lines and patient tissue samples.

Example 31 High Metastatic Potential Breast Cancer Versus Low Metastatic Breast Cancer Cells

The following tables summarize polynucleotides that represent genes that are differentially expressed between high metastatic potential and low metastatic potential breast cancer cells.

TABLE 44 High metastatic potential breast (lib3) > low metastatic potential (lib4) breast cancer cells SEQ ID NO: Lib3 Clones Lib4 Clones Lib3/Lib4 7309 40 0 39 7634 60 3 20 7562 14 0 14 7452 10 0 10 7479 10 1 10 7254 10 1 10 6537 10 1 10 7434 10 0 10 7522 19 2 9 7643 9 1 9 7409 8 1 8 6937 8 1 8 7630 8 0 8 7599 8 0 8 6925 8 1 8 7504 8 0 8 7543 7 0 7 7485 7 0 7 6452 7 0 7 7588 7 0 7 7639 22 3 7 6895 7 0 7 7533 6 0 6 7347 6 0 6 7068 18 3 6 7578 6 0 6 7395 6 0 6 6205 24 4 6 7654 6 0 6 7451 6 0 6 7644 11 2 5 6346 10 2 5 7015 26 6 4 6454 36 12 3 7621 75 28 3 7253 49 17 3

TABLE 45 Low metastatic potential breast (lib4) > high metastatic potential breast cancer cells (lib3) SEQ ID NO: Lib3 Clones Lib4 Clones Lib4/Lib3 6344 0 58 59 6822 1 23 24 6110 1 19 19 6795 0 14 14 6859 1 14 14 6116 1 13 13 6175 1 13 13 6811 0 10 10 7087 0 8 8 7295 0 8 8 6803 0 7 7 7224 4 26 7 6987 0 6 6 7242 2 11 6 6827 7 44 6 7614 3 15 5 6436 3 13 4 7045 4 13 3 7343 7 18 3 7281 497 1216 3

Example 32 High Metastatic Potential Lung Cancer Versus Low Metastatic Lung Cancer Cells

The following summarizes polynucleotides that represent genes differentially expressed between high metastatic potential lung cancer cells and low metastatic potential lung cancer cells:

TABLE 46 High metastatic potential lung (lib8) > low metastatic potential lung (lib9) lung cancer cells SEQ ID Lib8 NO: Clones Lib9 Clones Lib8/Lib9 6246 31 0 43 6747 43 2 30 7394 14 1 20 6153 11 0 15 6721 7 0 10 7418 7 1 10 6132 7 0 10 6717 18 3 8 6311 6 1 8 6657 19 4 7 6343 5 0 7 6295 5 0 7 7094 5 0 7 6598 5 0 7 7478 8 2 6 7277 17 4 6 7405 8 2 6 7253 15 4 5 7356 14 5 4 7281 710 266 4 7621 21 10 3

TABLE 47 Low metastatic potential lung (lib9) > high metastatic potential lung (lib8) cancer cells SEQ ID Lib8 NO: Clones Lib9 Clones Lib9/Lib8 7020 1 13 9 6918 1 13 9 6824 1 12 9 6437 1 12 9 7623 3 31 7 6794 4 26 5 7045 2 15 5 6840 3 23 5 7069 8 27 2

Example 33 High Metastatic Potential Colon Cancer Versus Low Metastatic Colon Cancer Cells

Tables 48 and 49 summarize polynucleotides that represent genes differentially expressed between high metastatic potential and low metastatic potential colon cancer cells:

TABLE 48 High metastatic potential (lib1) > low metastatic potential (lib2) colon cancer cells SEQ ID Lib1 Lib2 NO: Clones Clones Lib1/Lib2 6344 67 2 31 6183 12 0 11 6794 11 0 10 6153 13 3 4 7020 24 10 2 7345 24 9 2

TABLE 49 Low metastatic potential (lib2) > high metastatic potential colon cancer (lib1) cells SEQ ID Lib2 NO: Lib1 Clones Clones Lib2/Lib1 7364 1 17 18 7210 0 15 16 7128 1 14 15 6205 5 60 13 7069 1 11 12 6187 1 11 12 7078 0 9 10 7363 3 28 10 6189 1 8 9 7652 1 8 9 7347 0 8 9 7302 2 17 9 6908 0 8 9 7350 0 7 8 7316 0 7 8 6862 0 7 8 7252 0 7 8 7103 0 7 8 7077 0 7 8 6858 0 7 8 6972 0 6 6 7330 2 11 6 7279 0 6 6 7140 2 12 6 6881 0 6 6 7165 3 17 6 6866 0 6 6 6874 0 6 6 6888 0 6 6 6918 2 10 5 7354 7 23 4 7320 7 17 3 7080 8 19 3 6937 10 28 3 6435 14 34 3 7309 11 29 3 7297 5 14 3 7288 22 48 2

Example 34 High Metastatic Potential Colon Cancer Patient Tissue Vs. Normal Patient Tissue

Table 50 summarizes polynucleotides that represent genes differentially expressed between high metastatic potential colon cancer cells and normal colon cells of patient tissue.

TABLE 50 High metastatic potential colon tissue (lib17) vs. normal colon tissue (lib15) SEQ ID Lib15 Lib17 NO: Clones Clones Lib17/Lib15 7518 1 13 12  7228 1 10 9 6826 1 9 8 7407 0 7 7 6174 9 48 5 6918 5 20 4 SEQ ID Lib15 Lib17 NO: Clones Clones Lib15/Lib17 6559 8 1 9

Example 35 High Tumor Potential Colon Tissue Vs. Metastasized Colon Cancer Tissue

The following table summarizes polynucleotides that represent genes differentially expressed between high tumor potential colon cancer cells and cells derived from high metastatic potential colon cells of a patient.

TABLE 51 High tumor potential colon tissue (lib16) vs. high metastatic colon tissue (lib17) SEQ ID Lib16 Lib17 NO: Clones Clones Lib16/Lib17 7281 14  4  4 SEQ ID Lib16 Lib17 NO: Clones Clones Lib17/Lib16 6918  2 20 10

Example 36 High Tumor Potential Colon Cancer Patient Tissue Versus Normal Patient

Tables 13 and 14 summarize polynucleotides that represent genes differentially expressed between high metastatic potential colon cancer cells and normal colon cells in patient tissue:

TABLE 52 Higher expression in tumor potential colon tissue (lib16) vs. normal colon tissue (lib15) SEQ ID Lib15 Lib16 NO: Clones Clones Lib16/Lib15 7407 0 8 8 6174 9 28 3

TABLE 53 Higher expression in normal colon tissue (lib15) vs. tumor potential colon tissue (lib16) SEQ ID Lib16 NO: Lib15 Clones Clones Lib15/Lib16 6559 8 0 8 7195 12 3 4

Example 37 Growth Factor-Stimulated Human Microvascular Endothelial Cells (HMEC) Relative to Untreated HMEC

The following tables summarize polynucleotides that represent genes differentially expressed between growth factor-treated and untreated HMEC.

TABLE 54 Higher expression in bFGF treated HMEC (lib13) vs. untreated HMEC (lib12) SEQ ID Lib12 NO: Clones Lib13 Clones Lib13/Lib12 7616 9 23 3 7634 17 35 2

TABLE 55 Higher expression in VEGF treated HMEC (lib14) vs. untreated HMEC (lib12) SEQ ID Lib12 NO: Clones Lib14 Clones Lib14/Lib12 7250 2 12 6 7322 2 10 5 7634 17 38 2

Example 38 Polynucleotides Differentially Expressed in Human Prostate Cancer Cells Relative to Normal Human Prostate Cells

The following tables summarize identified polynucleotides that represent genes differentially expressed between prostate cancer cells and normal prostate cells:

TABLE 56 Higher expression in normal prostate cells (lib21) relative to prostate cancer cells (lib22) SEQ ID Lib21 NO: Clones Lib22 Clones Lib21/Lib22 7621 6 0 6 6344 116 51 2 7299 22 9 2

TABLE 57 Higher expression in prostate cancer cells (lib22) relative to normal prostate cells (lib21) SEQ ID Lib21 Lib22 NO: Clones Clones Lib22/Lib21 7309 0 34 35 6436 1 12 12 6795 0 11 11

Example 39 Differential Expression Across Multiple Libraries

A number of polynucleotide sequences have been identified that represent genes that are differentially expressed across multiple libraries. Expression of these sequences in a tissue or any origin can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. These polynucleotides can also serve as non-tissue specific markers of, for example, risk of metastasis of a tumor. Table 58 summarizes this data.

TABLE 58 Genes Differentially Expressed Across Multiple Library Comparisons SEQ ID NO: Cell or Tissue Sample and Cancer State Compared Ratio 6153 High Met Lung (lib8) > Low Met Lung (lib9) 15 6153 High Met Colon (lib1) > Low Met Colon (lib2) 4 6174 High Met Colon Tissue (lib17) > Normal Colon Tissue 5 (lib15) 6174 Normal Colon Tumor Tissue (lib16) > Normal Colon 3 Tissue (lib15) 6205 High Met Breast (lib3) > Low Met Breast (lib4) 6 6205 Low Met Colon (lib2) > High Met Colon (lib1) 13 6344 High Met Colon (lib1) > Low Met Colon (lib2) 31 6344 Normal Prostate (lib21) > Prostate Cancer (lib22) 2 6344 Low Met Breast (lib4) > High Met Breast (lib3) 59 6436 Prostate Cancer (lib22) > Normal Prostate (lib21) 12 6436 Low Met Breast (lib4)> High Met Breast (lib3) 4 6559 Normal Colon Tissue (lib15) > High Met Colon 9 Tissue (lib17) 6559 Normal Colon Tissue (lib15) > Normal Colon 8 Tumor Tissue (lib16) 6794 High Met Colon (lib1) > Low Met Colon (lib2) 10 6794 Low Met Lung (lib9) > High Met Lung (lib8) 5 6795 Low Met Breast (lib4) > High Met Breast (lib3) 14 6795 Prostate Cancer (lib22) > Normal Prostate (lib21) 11 6918 High Met Colon Tissue (lib17) > Normal Colon 10 Tumor Tissue (lib16) 6918 Low Met Lung (lib9) > High Met Lung (lib8) 9 6918 Low Met Colon (lib2) > High Met Colon (lib1) 5 6918 High Met Colon Tissue (lib17) > Normal 4 Colon Tissue (lib15) 6937 High Met Breast (lib3) > Low Met Breast (lib4) 8 6937 Low Met Colon (lib2) > High Met Colon (lib1) 3 7020 High Met Colon (lib1) > Low Met Colon (lib2) 2 7020 Low Met Lung (lib9) > High Met Lung (lib8) 9 7045 Low Met Lung (lib9) > High Met Lung (lib8) 5 7045 Low Met Breast (lib4) > High Met Breast (lib3) 3 7069 Low Met Colon (lib2) > High Met Colon (lib1) 12 7069 Low Met Lung (lib9) > High Met Lung (lib8) 2 7253 High Met Lung (lib8) > Low Met Lung (lib9) 5 7253 High Met Breast (lib3) > Low Met Breast (lib4) 3 7281 Normal Colon Tumor Tissue (lib16) > High Met 4 Colon Tissue (lib17) 7281 High Met Lung (lib8) > Low Met Lung (lib9) 4 7281 Low Met Breast (lib4) > High Met Breast (lib3) 3 7309 High Met Breast (lib3) > Low Met Breast (lib4) 39 7309 Prostate Cancer (lib22) > Normal Prostate (lib21) 35 7309 Low Met Colon (lib2) > High Met Colon (lib1) 3 7347 High Met Breast (lib3) > Low Met Breast (lib4) 6 7347 Low Met Colon (lib2) > High Met Colon (lib1) 9 7407 Normal Colon Tumor Tissue (lib16) > Normal 8 Colon Tissue (lib15) 7407 High Met Colon Tissue (lib17) > Normal 7 Colon Tissue (lib15) 7621 Normal Prostate (lib21) > Prostate Cancer (lib22) 6 7621 High Met Lung (lib8) > Low Met Lung (lib9) 3 7621 High Met Breast (lib3) > Low Met Breast (lib4) 3 7634 High Met Breast (lib3) > Low Met Breast (lib4) 20 7634 HMEC-VEGF (lib14) > HMEC (lib12) 2 7634 HMEC-bFGF (lib13) > HMEC (lib12) 2 Key for Table 58: High Met = high metastatic potential; Low Met = low metastatic potential; met = metastasized; tumor = non-metastasized tumor; HMEC = human microvascular endothelial cell; bFGF = bFGF treated; VEGF = VEGF treated.

Example 40 Identification of Contiguous Sequences Having a Polynucleotide of the Invention

The novel polynucleotides were used to screen publicly available and proprietary databases to determine if any of the polynucleotides of SEQ ID NOS:8707-8803 would facilitate identification of a contiguous sequence, e.g. the polynucleotides would provide sequence that would result in 5′ extension of another DNA sequence, resulting in production of a longer contiguous sequence composed of the provided polynucleotide and the other DNA sequence(s). Contiging was performed using the Gelmerge application (default settings) of GCG from the Univ. of Wisconsin.

Using these parameters, 97 contiged sequences were generated. These contiged sequences are provided as SEQ ID NOS: 8707-8803 (see Table 41C). Table 41C provides the SEQ ID NO of the contig sequence, the name of the sequence used to create the contig, and the accession number of the publicly available tentative human consensus (THC) sequence used with the sequence of the corresponding sequence name to provide the contig. The sequence name of Table 41C can be correlated with the SEQ ID NO: of the polynucleotide of the invention using Tables 41A and 41B.

TABLE 41C SEQ ID THC Accession NO: Sequence Name No. 8707 RTA00000587F.p.24.1.Seq THC226834 8708 RTA00000629F.1.02.1.Seq THC210324 8709 RTA00000623F.n.17.1.Seq THC208388 8710 RTA00000593F.i.08.2.Seq H91190 8711 RTA00000622F.b.03.1.Seq AA554045 8712 RTA00000618F.e.06.1.Seq THC226692 8713 RTA00000592F.o.02.1.Seq AA099789 8714 RTA00000618F.c.04.1.Seq THC222808 8715 RTA00000590F.i.01.1.Seq THC173163 8716 RTA00000606F.o.14.1.Seq THC223717 8717 RTA00000626F.d.07.1.Seq THC234888 8718 RTA00000587F.1.08.1.Seq THC104384 8719 RTA00000586F.a.13.1.Seq THC140691 8720 RTA00000617F.a.17.1.Seq THC221850 8721 RTA00000615F.b.23.1.Seq THC205191 8722 RTA00000632F.f.10.1.Seq N39216 8723 RTA00000607F.o.13.2.Seq THC233619 8724 RTA00000622F.c.12.1.Seq THC118482 8725 RTA00000625F.b.07.1.Seq THC223154 8726 RTA00000587F.j.01.1.Seq H63018 8727 RTA00000608F.i.15.1.Seq THC216448 8728 RTA00000592F.j.06.1.Seq THC148215 8729 RTA00000589F.b.14.1.Seq THC158020 8730 RTA00000633F.g.19.1.Seq THC202541 8731 RTA00000620F.o.07.1.Seq THC155200 8732 RTA00000586F.p.01.1.Seq AA558590 8733 RTA00000630F.1.10.1.Seq THC204748 8734 RTA00000626F.c.13.1.Seq AA159259 8735 RTA00000591F.m.06.1.Seq THC227858 8736 RTA00000630F.i.11.1.Seq THC228806 8737 RTA00000621F.h.08.1.Seq THC163604 8738 RTA00000589F.d.10.1.Seq THC177076 8739 RTA00000597F.p.01.1.Seq THC210746 8740 RTA00000619F.c.13.1.Seq R57955 8741 RTA00000607F.c.07.2.Seq THC208762 8742 RTA00000595F.b.02.1.Seq THC233682 8743 RTA00000631F.h.04.1.Seq THC223281 8744 RTA00000596F.p.18.1.Seq THC197103 8745 RTA00000586F.o.13.1.Seq THC222729 8746 RTA00000610F.p.17.1.Seq EST19015 8747 RTA00000596F.c.05.1.Seq EST72617 8748 RTA00000632F.j.19.1.Seq THC90741 8749 RTA00000607F.e.23.2.Seq AA639216 8750 RTA00000628F.b.19.1.Seq THC118075 8751 RTA00000609F.d.13.1.Seq THC195579 8752 RTA00000621F.k.03.1.Seq EST70278 8753 RTA00000592F.1.04.1.Seq THC91941 8754 RTA00000592F.k.09.1.Seq THC229803 8755 RTA00000622F.e.17.1.Seq R57425 8756 RTA00000628F.g.13.1.Seq THC176706 8757 RTA00000592F.k.23.1.Seq THC232202 8758 RTA00000609F.m.04.2.Seq AA507611 8759 RTA00000626F.b.04.1.Seq EST69420 8760 RTA00000591F.m.01.1.Seq H41850 8761 RTA00000608F.n.23.1.Seq THC214886 8762 RTA00000583F.d.19.1.Seq THC229251 8763 RTA00000621F.p.15.1.Seq THC212450 8764 RTA00000583F.n.05.1.Seq AA252468 8765 RTA00000597F.f.17.1.Seq THC219322 8766 RTA00000606F.1.10.1.Seq THC225232 8767 RTA00000618F.n.14.1.Seq THC216591 8768 RTA00000612F.h.05.3.Seq THC158250 8769 RTA00000619F.a.24.1.Seq AA437370 8770 RTA00000617F.k.13.1.Seq AA244445 8771 RTA00000623F.h.07.1.Seq THC212330 8772 RTA00000620F.e.01.1.Seq THC167493 8773 RTA00000620F.h.10.1.Seq THC232456 8774 RTA00000589F.e.21.2.Seq THC208239 8775 RTA00000626F.b.22.1.Seq THC225644 8776 RTA00000620F.i.16.1.Seq AA536090 8777 RTA00000613F.c.17.1.Seq THC92470 8778 RTA00000621F.c.12.1.Seq THC156244 8779 RTA00000618F.b.17.1.Seq THC209838 8780 RTA00000585F.d.16.1.Seq THC211870 8781 RTA00000592F.a.06.1.Seq THC233200 8782 RTA00000583F.p.08.1.Seq THC196844 8783 RTA00000622F.h.21.1.Seq EST12698 8784 RTA00000591F.h.03.1.Seq THC213771 8785 RTA00000620F.g.22.1.Seq THC224063 8786 RTA00000588F.l.20.2.Seq R84876 8787 RTA00000614F.a.20.1.Seq R84876 8788 RTA00000611F.n.14.3.Seq THC200742 8789 RTA00000619F.f.23.1.Seq THC227573 8790 RTA00000608F.g.24.1.Seq T93977 8791 RTA00000595F.o.01.2.Seq EST61392 8792 RTA00000608F.b.23.1.Seq THC161665 8793 RTA00000606F.o.23.1.Seq AA464645 8794 RTA00000588F.i.22.3.Seq THC162216 8795 RTA00000610F.i.13.1.Seq AA595068 8796 RTA00000608F.b.15.1.Seq EST11866 8797 RTA00000597F.e.16.1.Seq N88730 8798 RTA00000610F.h.13.1.Seq THC195895 8799 RTA00000611F.h.21.2.Seq EST46722 8800 RTA00000584F.b.06.1.Seq EST02998 8801 RTA00000584F.b.06.2.Seq EST02998 8802 RTA00000608F.j.05.1.Seq EST60433 8803 RTA00000588F.b.03.1.Seq THC164651

The contiged sequences (SEQ ID NOS: 8707-8803) thus represent longer sequences that encompass a polynucleotide sequence of the invention. The contiged sequences were then translated in all three reading frames to determine the best alignment with individual sequences using the BLAST programs as described above. The sequences were masked using the XBLAST program for masking low complexity as described above in Example 27. Several of the contiged sequences were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 42B, inserted prior to claims). Thus the invention encompasses fragments, fusions, and variants of such polynucleotides that retain biological activity associated with the protein family and/or functional domain identified herein.

Descriptions of the profiles for the indicated protein families and functional domains are provided 3 above. A description of the profile for PR55 is provided below.

Protein Phosphatase 2A Regulatory Subunit PR55 (PR55). Several of the contigs correspond to a sequence encoding a protein comprising a protein phosphatase 2A (PP2A) regulatory subunit PR55. PP2A is a serine/threonine phosphatase involved in many aspects of cellular function including the regulation of metabolic enzymes and proteins involved in signal transduction. PP2A is a trimeric enzyme comprising a core composed of a catalytic subunit associated with a 65 Kd regulatory subunit (PR65, also called subunit A). This complex associates with a third variable subunit (subunit B), which confers distinct properties to the holoenzyme (Mayer-Jaekel et al. Trends Cell Biol. (1994) 4:287-291). One of the forms of the variable subunit is a 55 Kd protein (PR55) which is highly conserved in mammals and may facilitate substrate recognition or targeting the enzyme complex to the appropriate subcellular compartment. The PR55 subunit comprises two conserved sequences of 15 residues; one located in the N-terminal region, the other in the center of the protein.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Deposit Information. The following materials were deposited with the American Type Culture Collection (CMCC=Chiron Master Culture Collection).

TABLE 59 Cell Lines Deposited with ATCC CMCC Cell Line Deposit Date ATCC Accession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containing specific clones, were assigned an “ES” number (internal reference) and deposited with the ATCC. Table 60 below provides the ATCC Accession Nos. of the ES deposits, all of which were deposited on or before May 13, 1999. The names of the clones contained within each of these deposits are provided in the tables numbered 61-63 (inserted before the claims).

TABLE 60 Pools of Clones and Libraries Deposited with ATCC on or before May 14, 1999 ES # ATCC Accession # 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

The deposits described herein are provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where the ATCC deposit is composed of a pool of cDNA clones or a library of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones in the pool or library were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

TABLE 61 Deposits of Pooled Clones ES34 ES35 ES36 ES37 M00006992C:G02 M00005468A:D08 M00005452C:A02 M00022171D:B08 M00006756D:E10 M00021892B:H03 M00001382C:C09 M00008061A:F02 M00003984C:F04 M00001390A:C06 M00004841C:B09 M00003820C:A09 M00007125D:E03 M00022074D:F11 M00001441D:H05 M00022109B:A11 M00006650A:A10 M00005460B:D02 M00022716D:D08 M00005342D:F03 M00001452B:H06 M00022423B:D03 M00022828C:E04 M00022070B:C10 M00022972D:C10 M00007140A:F11 M00004350B:F06 M00006966B:B09 M00022305C:A01 M00004081B:C11 M00005685B:D08 M00022381C:C12 M00007010B:H01 M00005480A:H12 M00004190A:A09 M00003991B:B05 M00021946D:C11 M00008015D:E09 M00004054D:D02 M00022404D:G05 ES38 ES39 ES40 ES41 M00021912B:H11 M00007118B:B04 M00006993B:B09 M00007974B:C11 M00005378C:A10 M00007019A:B01 M00004242C:C01 M00021860B:G06 M00022578C:B07 M00021682B:D12 M00007986C:C05 M00006927C:F12 M00005513A:D08 M00005411D:A03 M00004115A:G09 M00022582C:E12 M00022176C:A08 M00006641C:H02 M00022600C:A06 M00006618C:G08 M00006822D:F07 M00007041B:C05 M00005384A:A01 M00005450B:B01 M00004031A:B04 M00005444B:E11 M00021667D:E03 M00001417B:E01 M00021927D:D12 M00022745B:G02 M00008078C:C06 M00003825B:A05 M00001553D:B06 M00022685A:F11 M00007985A:B09 M00001370B:B04 M00022404B:H05 M00004446A:G01 M00007953B:B03 M00006727B:E09 ES42 ES43 ES44 ES45 M00001478A:B06 M00006923B:H08 M00006615B:F05 M00005468D:F04 M00003972B:A11 M00005377D:F11 M00005486C:B03 M00006720C:C11 M00005477C:D08 M00006640B:H09 M00007124C:A11 M00005817D:E12 M00006745A:A01 M00005404C:F02 M00006995D:A03 M00001669B:A03 M00007090B:A02 M00004030A:G12 M00007149D:G06 M00003998A:G12 M00007152A:B04 M00006704D:D03 M00006990D:D06 M00004045A:B12 M00006953B:H10 M00006810D:A05 M00005530B:E04 M00004130D:E04 M00005399D:B02 M00005481C:A05 M00003918C:E07 M00004160A:D07 M00006987B:F04 M00005411A:C07 M00007163A:B10 M00001655A:F07 M00005772A:F03 M00003970A:G10 M00005485C:A03 M00001468D:D11 ES46 M00004217A:A05 M00004183D:B07 M00001415D:A05 M00004158C:F03 M00004031D:G02

TABLE 62 Library Deposits ES47 ES48 ES49 ES50 M00001399D:F09 M00004217D:G10 M00004508A:G12 M00021653A:G07 M00001455A:C03 M00004218C:G10 M00004508B:G02 M00021654C:A02 M00001456C:F02 M00004252D:H08 M00001432B:H08 M00021660C:G04 M00001487D:G03 M00004253B:A10 M00001432C:G01 M00021665A:D04 M00001539B:B01 M00004253B:F06 M00003992D:G01 M00021670B:G11 M00001565A:A02 M00004253C:E10 M00005326B:F03 M00021678A:B08 M00001572C:E07 M00004260A:B07 M00005332A:H10 M00021680B:C01 M00001582D:B10 M00004260C:A12 M00005342A:C04 M00021681C:B10 M00001584C:A03 M00004260C:E10 M00005342A:D04 M00021690D:E05 M00001586A:F09 M00001339B:A03 M00005349B:G01 M00021692A:E03 M00001588D:H08 M00001342C:A04 M00005352B:D02 M00021692C:E06 M00001610B:A01 M00001344D:G11 M00005354C:E02 M00021694B:A07 M00001618B:F02 M00001345A:A12 M00005356A:D09 M00021698B:B12 M00001618C:E06 M00001347A:G06 M00005359D:G07 M00021828A:C08 M00001621C:A04 M00001347B:H01 M00005378A:A08 M00021841C:D07 M00001626B:H05 M00001353B:D11 M00005383D:D06 M00021859A:D04 M00001641B:G05 M00001355B:A01 M00005383D:E07 M00021861C:A02 M00001648C:F06 M00001358D:D09 M00005385C:G05 M00021862A:A04 M00001649D:H05 M00001359A:B07 M00005388D:F09 M00021862D:F01 M00001656D:F11 M00001362A:C10 M00005390B:G10 M00021886D:E04 M00001660A:F10 M00001362B:A09 M00005397C:B03 M00021897B:A06 M00001669A:H11 M00001365D:D12 M00005399A:D01 M00021905A:G05 M00003741A:E01 M00001365D:H09 M00005409D:C02 M00021905B:A01 M00003745C:E03 M00001370A:G09 M00005415C:G08 M00021906C:G11 M00003746A:E01 M00001370B:B12 M00005417A:E10 M00021910A:C10 M00003748B:B06 M00001374D:D09 M00005442D:C05 M00021927A:C11 M00003749B:C08 M00001376B:C11 M00005446A:G01 M00021927B:F01 M00003749D:G07 M00001377A:D03 M00005446C:D12 M00021932C:C05 M00003752A:B06 M00001377A:E01 M00005454C:H12 M00021932C:G10 M00003752D:D09 M00001377C:B08 M00005455A:D01 M00021947A:C01 M00003753C:B01 M00001387A:A04 M00005455A:G03 M00021952B:F11 M00003754C:F01 M00001387D:C07 M00005462C:B02 M00021954A:A03 M00003756C:C08 M00001389B:B06 M00005469D:C11 M00021964A:C04 M00003759A:E10 M00001390A:H01 M00005480C:B12 M00021967D:E08 M00003762A:D11 M00001399C:E10 M00005483D:A12 M00021977D:E02 M00003763B:D03 M00001401D:D04 M00005484A:D09 M00021978A:F08 M00003763D:F06 M00001402D:C07 M00005491B:C03 M00021982C:F08 M00003765D:E02 M00001402D:H03 M00005493B:C08 M00021983B:B03 M00003766B:G04 M00001403B:A01 M00005494D:F11 M00021983D:B10 M00003767C:F04 M00001405D:F05 M00005496C:A01 M00022005C:G03 M00003769B:A04 M00001406C:A11 M00005496D:A10 M00022032A:E07 M00003769D:G12 M00001406D:H01 M00005497B:H07 M00022049A:A02 M00003770D:C07 M00001407B:A08 M00005497C:C07 M00022049A:D06 M00003771A:G09 M00001407D:H11 M00005497C:C12 M00022054D:C05 M00003771D:A10 M00001411A:D01 M00005497C:E03 M00022064C:H07 M00003773A:C09 M00001411C:G02 M00005498B:F08 M00022067D:C05 M00003773B:E09 M00001412A:A11 M00005498C:G05 M00022068B:H11 M00003773B:G08 M00001415D:E12 M00005508B:B04 M00022068D:D12 M00003773C:G06 M00001417C:E02 M00005524C:B01 M00022069D:G02 M00003773D:C02 M00001421A:H07 M00005528D:A10 M00022071B:D05 M00003789C:E03 M00001422D:D02 M00005530B:D03 M00022071C:D09 M00003790B:F12 M00001423C:D06 M00005534B:H10 M00022075D:F05 M00003793C:D11 M00001424A:H09 M00005548B:E03 M00022081C:G11 M00003796B:C07 M00001425C:E10 M00005550B:D09 M00022084B:F04 M00003797D:H06 M00001426A:F09 M00005565C:A08 M00022085C:C04 M00003801D:F05 M00001426D:D09 M00005589C:B03 M00022090A:G08 M00003805A:G05 M00001431A:C10 M00005616B:D05 M00022093A:A05 M00003808C:D09 M00001431A:E05 M00005620C:C05 M00022093D:B10 M00003809A:A12 M00001432A:F12 M00005621A:G10 M00022094B:G10 M00003809A:H12 M00001432B:H08 M00005621D:F01 M00022106C:F04 M00003813D:A06 M00001432C:G01 M00005631A:A11 M00022110A:E04 M00003818A:F09 M00001433A:C07 M00005632C:D06 M00022114C:B02 M00003818B:A01 M00001434A:A01 M00005637B:D12 M00022117C:G07 M00003819D:G09 M00001435A:F03 M00005642B:C03 M00022128A:D04 M00003821C:E04 M00001435A:G01 M00005647D:D09 M00022139A:C01 M00003822A:G05 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M00004263D:F06 M00007134C:F07 M00022824C:H11 M00004115A:F01 M00004272D:D02 M00007137D:C10 M00022835C:E06 M00004117B:F01 M00004273D:E11 M00007140D:C12 M00022854D:H07 M00004120A:C02 M00004277D:C08 M00007150A:C09 M00022856A:D02 M00004126B:G02 M00004281B:B05 M00007150A:H06 M00022856B:F04 M00004129A:H08 M00004283C:D03 M00007154A:E04 M00022856C:B11 M00004130C:A09 M00004285B:E01 M00007163A:F11 M00022893C:H11 M00004133D:A01 M00004297D:E08 M00007163B:A12 M00022897A:F04 M00004178B:F06 M00004298B:D04 M00007166B:E06 M00022900D:E08 M00004180B:F04 M00004308A:E06 M00007170D:A10 M00022900D:G03 M00004184B:F11 M00004324B:D09 M00007172A:A05 M00004191B:G01 M00004328A:H06 M00007172D:C08 M00004193A:C07 M00004329C:F11 M00007188A:D03 M00004193C:H01 M00004331D:H08 M00007189D:A09 M00004199D:C02 M00004332C:E09 M00007193D:A04 M00004200A:A09 M00004337D:G08 M00007195B:B02 M00004200A:G06 M00004345A:H06 M00007198C:A10 M00004200D:A07 M00004383A:F02 M00007199D:B07 M00004201D:C11 M00004385C:B11 M00007204C:F09 M00004201D:E12 M00004388C:D05 M00007929B:H10 M00004202B:A02 M00004406A:H03 M00007961A:B01 M00004204A:D04 M00004408D:A10 M00007964B:D10 M00004204A:D10 M00004410A:E03 M00007971A:B04 M00004204B:A04 M00004412B:E03 M00007977C:E08 M00004210A:B09 M00004421A:G04 M00007995D:E06 M00004216D:E10 M00004447D:D10 M00008074D:C01 M00004217A:A11 M00004460B:H09 M00008094A:E10 M00004465C:B10 M00021611D:D05 M00004465C:B12 M00021611D:H03 M00004467A:F09 M00021614B:G12 M00004467D:F09 M00021618D:D07 M00004491D:D07 M00021624A:D07 M00004497C:E09 M00021624B:A03 M00004501A:G06 M00021625A:C07 M00004506C:H10 M00021629D:D05

TABLE 63 Library Deposits ES51 ES52 ES53 ES54 M00001448A:D05 M00001439B:E02 M00006621A:G10 M00021640A:G03 M00001458B:F06 M00001443A:E02 M00006626A:G11 M00021657B:C08 M00001530A:D11 M00001443D:C03 M00006629D:D04 M00021690B:B06 M00001563C:D06 M00001444A:G12 M00006630B:H06 M00021690C:B07 M00001564C:D04 M00001445B:E03 M00006631D:B02 M00022071C:C09 M00001569B:F04 M00001451B:H11 M00006631D:C04 M00022081C:B11 M00001575A:H02 M00001452B:F09 M00006631D:E09 M00022085C:A07 M00001589C:D12 M00001488B:H02 M00006635C:B10 M00022091B:B07 M00001589D:G10 M00001491D:E07 M00006636A:E06 M00022122D:D06 M00001590D:A07 M00001496C:H10 M00006636D:A05 M00022150D:D11 M00001598C:D10 M00001499A:D01 M00006636D:F11 M00022154A:C01 M00001599A:H09 M00001499A:D05 M00006640A:B01 M00022170D:H07 M00001609A:B12 M00001499B:H05 M00006640B:F05 M00022365A:A01 M00001614C:G04 M00001500B:H07 M00006640D:H08 M00022389B:H04 M00001626C:C10 M00001504C:H11 M00006641A:B03 M00022439A:E07 M00001634C:E12 M00001506D:A11 M00006643A:E10 M00022449D:F06 M00001639A:A04 M00001543A:D03 M00006644C:E09 M00022458B:E06 M00001640A:F02 M00001543A:F01 M00006648C:E04 M00022474A:H09 M00001640A:F04 M00001548C:A09 M00006650A:B11 M00022480B:E07 M00001647C:C07 M00001555D:F11 M00006656C:C10 M00022489C:A08 M00001649B:E08 M00001557B:D10 M00006664B:B04 M00022490C:A08 M00001654D:F06 M00001597A:C07 M00006664D:H09 M00022490C:C01 M00001658B:C07 M00001604B:D09 M00006665A:F07 M00022493C:B07 M00001659D:G08 M00001605D:G01 M00006665B:D10 M00022493C:C06 M00001663C:C03 M00001621D:B09 M00006674B:F04 M00022498C:C08 M00001675C:B03 M00001622C:F06 M00006676B:F11 M00022514A:D04 M00001677A:A06 M00001624A:A09 M00006676D:D11 M00022515D:C04 M00001677A:A12 M00001640D:C10 M00006679C:D07 M00022549B:G07 M00001678D:A12 M00001645B:C09 M00006681C:G04 M00022557B:A08 M00001679C:F03 M00003782D:F04 M00006695B:F08 M00022565C:H02 M00001681A:H09 M00003783C:A06 M00006698B:E06 M00022578D:A08 M00001687C:A06 M00003786D:C06 M00006699B:C07 M00022597B:F11 M00001693D:F07 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M00022960D:E08 M00003820A:H04 M00004134A:H04 M00006758D:C01 M00022963A:D11 M00003820D:E02 M00004134C:B11 M00006760D:G12 M00022968A:F02 M00003824B:D06 M00004140B:B01 M00006763B:B11 M00022980B:E11 M00003825B:D12 M00004143C:F08 M00006769D:A04 M00022980C:A09 M00003826B:D01 M00004144D:B06 M00006770B:C05 M00022993A:F02 M00003829A:E02 M00004152C:E01 M00006771A:E06 M00023003C:A03 M00003832B:G03 M00004159D:H07 M00006771A:H07 M00023011A:A06 M00003833D:D06 M00004160A:A01 M00006771B:A09 M00023021A:H08 M00003835A:E03 M00004161B:A12 M00006771B:F03 M00023023A:B12 M00003837C:F05 M00004163A:D11 M00006774D:C01 M00023028A:A02 M00003839C:B05 M00004164D:D02 M00006777B:D10 M00023033A:E10 M00003845A:A05 M00004165C:E09 M00006779B:A11 M00023034C:E05 M00003846D:C12 M00004166A:F02 M00006779D:D03 M00023036D:C04 M00003857C:A03 M00004167C:F10 M00006780A:H12 M00023094A:C04 M00003858A:D01 M00004169A:B11 M00006789C:F04 M00023103A:E11 M00003860B:A07 M00004200B:B04 M00006790D:A05 M00006754B:D05 M00003868B:C07 M00004222A:H10 M00006796A:H10 M00003881D:D09 M00004223D:D07 M00006797B:D12 M00003883D:C03 M00004225D:F01 M00006801A:G05 M00003884B:E06 M00004228C:D11 M00006805A:E11 M00003886C:D10 M00004229C:G11 M00006805A:H09 M00003903C:A12 M00004239C:A07 M00006805B:C04 M00003912C:H01 M00004239C:C09 M00006807D:D08 M00003915B:G07 M00004240D:E06 M00006813A:C04 M00003920D:D09 M00004241B:B01 M00006822D:D05 M00003926B:E03 M00004243C:E10 M00006825C:D06 M00003934D:F01 M00004266A:F10 M00006831B:B04 M00003958C:C10 M00004266B:H06 M00006832A:F05 M00003965A:F07 M00004268C:F08 M00006832D:F10 M00003972C:F02 M00004268D:G07 M00006833B:E11 M00003974B:A04 M00004269A:B11 M00006872B:G01 M00003974C:A05 M00004269D:E08 M00006875D:D10 M00003975B:H09 M00004276C:E12 M00006879D:A10 M00003976C:C05 M00004277B:C06 M00006882D:F03 M00003980C:A11 M00004277C:H11 M00006884D:D06 M00003987A:C07 M00004279D:E02 M00006908C:A05 M00003988B:C10 M00004281B:B03 M00006921B:C02 M00003988C:A06 M00004284B:F07 M00006921B:E03 M00003989C:F01 M00004287B:B12 M00006949B:F03 M00004028C:D01 M00004287C:B06 M00006960A:G11 M00004029A:E01 M00004297D:B08 M00006966D:G03 M00004030A:E09 M00004332B:D02 M00006974B:D06 M00004031A:G05 M00004332B:E11 M00007013B:F02 M00004032D:D03 M00004346B:D06 M00007014D:C05 M00004033C:D10 M00004389C:E01 M00007014D:D04 M00004034A:E08 M00004403A:B05 M00007030A:G01 M00004035A:A10 M00004407D:B09 M00007030C:F08 M00004035B:H11 M00004419D:G01 M00007053B:C07 M00004035D:C05 M00004449D:H01 M00007065B:B12 M00004037B:A09 M00004463C:F11 M00007065D:C01 M00004037C:C05 M00004466A:E09 M00007075C:D08 M00004037D:B05 M00004469A:C12 M00007085A:B07 M00004044A:F08 M00004470C:A02 M00007118C:G02 M00004068A:F02 M00004498B:E01 M00007119B:H10 M00004068B:D04 M00004509A:H02 M00004824C:G09 M00004068D:B01 M00004605C:A09 M00004826A:E09 M00004069B:B01 M00004609C:C11 M00004839C:B01 M00004073D:E01 M00001378B:F06 M00004840C:F02 M00004075A:G10 M00005294C:G08 M00004840C:H05 M00004075C:C09 M00005294D:H02 M00004845D:E11 M00004076A:E02 M00005330C:F09 M00004846A:D02 M00004077D:D10 M00005333C:C08 M00004846D:H09 M00004078A:F03 M00005342B:G10 M00004854A:C09 M00004078C:A08 M00005352C:G09 M00004858D:E06 M00004084A:D11 M00005352D:E06 M00004999A:F01 M00004086A:A03 M00005353B:B09 M00004999B:D12 M00004086D:A07 M00005359B:G01 M00004999D:E01 M00004088A:F12 M00005359D:H08 M00005004B:C11 M00004089A:F02 M00005377A:A04 M00005005C:E06 M00004089A:G03 M00005377A:D05 M00005009B:A02 M00004093A:F03 M00005385C:D08 M00005015D:D11 M00004097C:A03 M00005388A:F07 M00005457D:C08 M00004102B:B04 M00005388D:B11 M00005519B:H04 M00004102C:F07 M00005392C:C04 M00005519C:F08 M00004103B:C09 M00005393A:E11 M00005531B:A03 M00004103C:F11 M00005394A:G07 M00005535B:F06 M00004104A:H09 M00005396B:C04 M00005587B:H02 M00004104D:C09 M00005399B:F02 M00005685A:A04 M00004108A:D04 M00005400A:D02 M00005706D:A09 M00004109B:A01 M00005403D:E11 M00005711A:H01 M00004126D:B11 M00005406D:B08 M00005798B:C11 M00004133C:B02 M00005411D:E05 M00005799C:C12 M00004182D:H03 M00005415D:G02 M00005805D:E06 M00004183A:D06 M00005417C:E10 M00005827B:H08 M00004186B:E05 M00005419A:D05 M00005828D:C09 M00004187C:H09 M00005419C:D09 M00005837A:D12 M00004188A:E05 M00005443D:C12 M00006751B:B11 M00004188A:E10 M00005447B:D02 M00006754B:D05 M00004190A:C12 M00005448D:E08 M00006756B:B08 M00004190C:G07 M00005450A:A02 M00006757D:E04 M00004190D:A10 M00005450A:B10 M00006758A:B12 M00004190D:G12 M00005450D:D02 M00006758D:C04 M00004198D:H04 M00005451A:E03 M00006834A:C08 M00004202B:F04 M00005456B:B07 M00006835B:F04 M00004202B:G09 M00005456B:E03 M00006837C:G06 M00004206C:G11 M00005460A:B10 M00006841D:A08 M00004213A:H12 M00005465C:H02 M00006855C:H02 M00004214A:D03 M00005466A:F12 M00006855D:H02 M00004218D:F12 M00005468B:D04 M00006859A:F06 M00004249C:E12 M00005470B:E01 M00006860B:H01 M00004249D:G02 M00005473D:E10 M00006886A:D06 M00004252D:A07 M00005483A:F05 M00006893C:B02 M00004253D:F09 M00005483D:A02 M00006893C:F02 M00004257C:A08 M00005487A:H01 M00006895D:E10 M00004262C:C01 M00005489A:F06 M00006917C:E07 M00001339B:E05 M00005493B:A12 M00006919B:C03 M00001341A:A11 M00005493B:E01 M00006923C:B01 M00001346A:B09 M00005497C:C10 M00006926A:H11 M00001346B:A07 M00005505A:C08 M00006934A:G02 M00001346B:G03 M00005508A:H01 M00006936B:E09 M00001346C:B07 M00005510B:D06 M00006936B:F10 M00001348A:G04 M00005528D:H06 M00006937B:F07 M00001348D:H08 M00005534A:G06 M00006937B:G09 M00001352C:E01 M00005539D:G07 M00006939B:E05 M00001362B:H09 M00005571A:E11 M00006953D:H11 M00001370A:B01 M00005619C:H10 M00006980A:F02 M00001370B:D04 M00005625D:C03 M00006986C:G11 M00001374C:C09 M00005626A:B11 M00006989B:C11 M00001376A:H02 M00005635B:A06 M00006990B:H09 M00001378B:F06 M00005635C:F11 M00006991A:E07 M00001380C:D10 M00005636C:D11 M00006991D:G07 M00001383C:C07 M00005637D:C05 M00006995C:A02 M00001384A:C09 M00005641B:E02 M00006997B:E06 M00001391D:A07 M00005645D:F08 M00006997D:B03 M00001391D:A09 M00005646C:B09 M00007006D:D04 M00001396C:G02 M00005646D:B03 M00007010B:C11 M00001397A:F10 M00005655D:C04 M00007010B:H03 M00001397B:E02 M00005703C:B01 M00007012B:D07 M00001397B:H11 M00005720B:D09 M00007031C:D01 M00001399D:F01 M00005722A:E09 M00007032A:F11 M00001400D:B08 M00005762D:A01 M00007033A:H05 M00001402C:E09 M00005783A:C05 M00007033D:F04 M00001406A:G12 M00005812C:F10 M00007036A:D02 M00001406D:B06 M00006581C:D02 M00007037B:D04 M00001408A:B02 M00006581D:H08 M00007084B:A05 M00001409C:D01 M00006582A:B09 M00007093A:F09 M00001411C:F02 M00006582D:E05 M00007099C:F09 M00001411D:C01 M00006592A:D03 M00007101A:A11 M00001412D:C03 M00006594D:F09 M00007107A:D11 M00001417B:C07 M00006596A:F07 M00007121C:H01 M00001417C:A09 M00006601D:F04 M00007129A:E04 M00001418A:C02 M00006604C:H10 M00007132B:B11 M00001421C:A03 M00006607B:E03 M00007134B:G07 M00001426A:C02 M00006607B:F04 M00007146D:G01 M00001427A:C05 M00006615D:F04 M00007148B:C06 M00001433A:F04 M00006616C:H09 M00007160C:B08 M00001434C:D05 M00006616D:C08 M00007161A:H03 M00001435C:H05 M00006617B:D09 M00007192C:H08 M00001438A:H10 M00006619B:C11 M00007200B:C02 M00001438B:H06 M00021619B:G10

Example 41 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from either human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863), KM12C (Morikawa et al. Cancer Res. (1988) 48:1943-1948), or MDA-MB-231 (Brinkley et al. Cancer Res. (1980) 40:3118-3129) was used to construct a cDNA library from mRNA isolated from the cells. Sequences expressed by these cell lines were isolated and analyzed; most sequences were about 275-300 nucleotides in length. The KM12L4-A cell line is derived from the KM12C cell line. The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246). The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma.

Example 42 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of various polynucleotides isolated from the Example 41 were assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 64 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 64 Description of cDNA Libraries No. of Library Clones in (lib #) Description Library 1 Human Colon Cell Line Km12 L4: High Metastatic Potential (derived 308731 from Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic Potential 284771 3 Human Breast Cancer Cell Line MDA-MB-231: High Metastatic 326937 Potential; micro-metastases in lung 4 Human Breast Cancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung Cancer Cell Line MV-522: High Metastatic Potential 223620 9 Human Lung Cancer Cell Line UCP-3: Low Metastatic Potential 312503 12 Human microvascular endothelial cells (HMEC) - UNTREATED 41938 (PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells (HMEC) - bFGF TREATED 42100 (PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells (HMEC) - VEGF TREATED 42825 (PCR (OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTED PCR (OligodT) 282722 cDNA library) 16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR (OligodT) 298831 cDNA library) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467 (MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED PCR (OligodT) 36216 cDNA library) 19 Colon Tumor - UC#3 Patient (MICRODISSECTED PCR (OligodT) 41388 cDNA library) 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 (MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived from normal prostate epithelium 164801 22 WOca Cells derived from Gleason Grade 4 prostate cancer epithelium 162088 23 Normal Lung Epithelium of Patient #1006 (MICRODISSECTED PCR 306198 (OligodT) cDNA library) 24 Primary tumor, Large Cell Carcinoma of Patient #1006 309349 (MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4 and KM12C cell lines are described in Example 41 above. The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al, Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cell lines were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974).

Using the methods and libraries described above, 37 of the isolated polynucleotides were identified as being differentially expressed across multiple libraries. Table 65 provides a list of these polynucleotides and their corresponding sequence names. The sequences of each of the above-referenced polynucleotides were determined using methods well known in the art. The sequences of the 37 polynucleotides, assigned SEQ ID NOS:8804-8840, are provided in the Sequence Listing below.

TABLE 65 Polynucleotides corresponding to differentially expressed genes SEQ ID NO. Sequence Name 8804 13905 8805 RTA00000281F.o.21.1 8806 RTA00000348R.d.10.1 8807 RTA00000177AF.d.22.3 8808 RTA00000684F.e.07.1 8809 RTA00000618F.p.24.1 8810 RTA00000596F.d.12.1 8811 RTA00000421F.d.20.1 8812 17090 8813 RTA00000161A.1.7.1 8814 RTA00000155A.k.14.1 8815 RTA00000163A.e.10.1 8816 RTA00000126A.o.15.2 8817  2546 8818 RTA00000144A.p.8.1 8819 RTA00000618F.k.16.1 8820 RTA00000742F.o.19.1 8821 RTA00000148A.o.18.1 8822 RTA00000619F.d.02.1 8823 RTA00000683F.1.19.1 8824 RTA00000172A.d.9.3 8825 RTA00000165A.d.16.1 8826 RTA00000188AR.d.05.1 8827 RTA00000183AF.n.14.1 8828 RTA00000346F.g.11.1 8829 RTA00000183AR.n.14.1 8830 RTA00000742F.g.08.1 8831 RTA00000689F.h.06.1 8832 RTA00000185AF.b.9.1 8833 RTA0000018SAF.b.9.2 8834 RTA00000192AR.o.8.2 8835 RTA00000192AF.o.8.1 8836 RTA00000685F.j.16.1 8837 RTA00000621F.i.13.2 8838 RTA00000685F.1.23.1 8839 16405 8840 028035A The differential expression data for these sequences is provided below.

Example 43 Genes Differentially Expressed Genes in Non-Metastatic or Low Metastatic Potential Cancer Cells Versus High Metastatic Potential Cancer Cells

The relative levels of expression of genes corresponding to SEQ ID NO:8804-8840 across various libraries described in Table 64 are summarized in Table 66 below.

TABLE 66 Genes Differentially Expressed Across Multiple Library Comparisons SEQ ID NO: Cell or Tissue Sample and Cancer State Compared RATIO 8804 Low Met Breast (lib4) > High Met Breast (lib3) 5.38 8804 Low Met Colon (lib2) > High Met Colon (lib1) 6.14 8805 Low Met Colon (lib2) > High Met Colon (lib1) 3.56 8805 Low Met Breast (lib4) > High Met Breast (lib3) 2.73 8805 Normal Prostate (lib21) > Prostate Cancer (lib 22) 4.92 8806 Low Met Colon (lib2) > High Met Colon (lib1) 3.52 8806 Low Met Breast (lib4) > High Met Breast (lib3) 4.3 8807 Low Met Colon (lib2) > High Met Colon (lib1) 3.52 8807 Low Met Breast (lib4) > High Met Breast (lib3) 4.3 8808 High Met Lung (lib8) > Low Met Lung (lib9) 3.35 8808 Low Met Colon (lib2) > High Met Colon (lib1) 3.47 8808 Low Met Breast (lib4) > High Met Breast (lib3) 30.24 8809 Low Met Breast (lib4) > High Met Breast (lib3) 30.24 8809 Low Met Colon (lib2) > High Met Colon (lib1) 3.47 8809 High Met Lung (lib8) > Low Met Lung (lib9) 3.35 8810 Low Met Colon (lib2) > High Met Colon (lib1) 3.47 8810 Low Met Breast (lib4) > High Met Breast (lib3) 30.24 8810 High Met Lung (lib8) > Low Met Lung (lib9) 3.35 8811 Low Met Breast (lib4) > High Met Breast (lib3) 2.42 8811 Low Met Colon (lib2) > High Met Colon (lib1) 2.63 8812 Low Met Colon (lib2) > High Met Colon (lib1) 2.49 8812 Low Met Breast (lib4) > High Met Breast (lib3) 2.19 8812 Low Met Lung (lib9) > High Met Lung (lib8) 3.07 8813 Low Met Breast (lib4) > High Met Breast (lib3) 41 8813 High Met Lung (lib8) > Low Met Lung (lib9) 2.29 8814 Low Met Breast (lib4) > High Met Breast (lib3) 7.35 8814 Normal Prostate (lib21) > Prostate Cancer (lib 22) 9.84 8815 High Met Breast (lib3) > Low Met Breast (lib4) 6.41 8815 High Met Colon (lib1) > Low Met Colon (lib2) 2.39 8816 High Met Colon (lib1) > Low Met Colon (lib2) 2.05 8816 High Met Breast (lib3) > Low Met Breast (lib4) 9.76 8817 Low Met Breast (lib4) > High Met Breast (lib3) 4.54 8817 High Met Lung (lib8) > Low Met Lung (lib9) 10.48 8817 Low Met Colon (lib2) > High Met Colon (lib1) 8.31 8818 Low Met Breast (lib4) > High Met Breast (lib3) 2.05 8818 Low Met Colon (lib2) > High Met Colon (lib1) 7.05 8819 Low Met Colon (lib2) > High Met Colon (lib1) 4.34 8819 Low Met Breast (lib4) > High Met Breast (lib3) 6.75 8820 Low Met Colon (lib2) > High Met Colon (lib1) 4.34 8820 Low Met Breast (lib4) > High Met Breast (lib3) 6.75 8821 Low Met Colon (lib2) > High Met Colon (lib1) 3.98 8821 Low Met Breast (lib4) > High Met Breast (lib3) 3.31 8821 Low Met Lung (lib9) > High Met Lung (lib8) 2.5 8822 Low Met Colon (lib2) > High Met Colon (lib1) 3.56 8822 Normal Prostate (lib21) > Prostate Cancer (lib 22) 4.92 8822 Low Met Breast (lib4) > High Met Breast (lib3) 2.73 8823 Normal Prostate (lib21) > Prostate Cancer (lib 22) 4.92 8823 Low Met Breast (lib4) > High Met Breast (lib3) 2.73 8823 Low Met Colon (lib2) > High Met Colon (lib1) 3.56 8824 Low Met Colon (lib2) > High Met Colon (lib1) 3.56 8824 Low Met Breast (lib4) > High Met Breast (lib3) 2.73 8824 Normal Prostate (lib21) > Prostate Cancer (lib 22) 4.92 8825 Low Met Colon (lib2) > High Met Colon (lib1) 3.52 8825 Low Met Breast (lib4) > High Met Breast (lib3) 3.55 8825 High Met Lung (lib8) > Low Met Lung (lib9) 17.7 8826 Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8826 Low Met Breast (lib4) > High Met Breast (lib3) 3.07 8827 Low Met Breast (lib4) > High Met Breast (lib3) 3.07 8827 Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8828 Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8828 Low Met Breast (lib4) > High Met Breast (lib3) 3.07 8829 Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8829 Low Met Breast (lib4) > High Met Breast (lib3) 3.07 8830 Low Met Colon (lib2) > High Met Colon (lib1) 3.25 8830 Low Met Breast (lib4) > High Met Breast (lib3) 3.07 8831 Low Met Colon (lib2) > High Met Colon (lib1) 2.86 8831 Low Met Breast (lib4) > High Met Breast (lib3) 8.14 8832 Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8832 Low Met Breast (lib4) > High Met Breast (lib3) 2.5 8833 Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8833 Low Met Breast (lib4) > High Met Breast (lib3) 2.5 8834 Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8834 Low Met Breast (lib4) > High Met Breast (lib3) 2.5 8835 Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8835 Low Met Breast (lib4) > High Met Breast (lib3) 2.5 8836 Low Met Colon (lib2) > High Met Colon (lib1) 2.14 8836 Low Met Breast (lib4) > High Met Breast (lib3) 2.27 8837 Normal Prostate (lib21) > Prostate Cancer (lib 22) 5.9 8837 Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8837 Low Met Breast (lib4) > High Met Breast (lib3) 2.18 8838 Normal Prostate (lib21) > Prostate Cancer (lib 22) 5.9 8838 Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8838 Low Met Breast (lib4) > High Met Breast (lib3) 2.18 8839 Low Met Colon (lib2) > High Met Colon (lib1) 2.1 8839 Low Met Breast (lib4) > High Met Breast (lib3) 2.18 8839 Normal Prostate (lib21) > Prostate Cancer (lib 22) 5.9 8840 Low Met Colon (lib2) > High Met Colon (lib1) 2.17 8840 Low Met Breast (lib4) > High Met Breast (lib3) 2.9 8840 Low Met Lung (lib9) > High Met Lung (lib8) 3.4 Key for Table 66: High Met = high metastatic potential; Low Met = low metastatic potential; met = metastasized; tumor = non-metastasized tumor

The relative expression levels of the genes corresponding to the polynucleotides above can be exploited in diagnostic and prognostic assays. For example, where the polynucleotide corresponds to a gene that is expressed at a relatively higher level in a low metastatic potential cell relative to a high metastatic potential cell (or at a relatively higher level in normal cells or nonmetastasized tumor cells relatively to metastatic or high metastatic potential cancerous cells), expression of the gene can serve as a marker indicating low risk of metastasis and may encode a suppressor of metastasis. Where the polynucleotide corresponds to a gene expressed at a relatively higher level in a high metastatic potential cell relative to a low metastatic potential cell, expression of the gene can serve as a marker of metastatic potential, indicating the need for more aggressive therapy.

Example 44 Identification of a Gene and Protein Encoded by the Polynucleotide

SEQ ID NOS:8804-8840 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in either the GenBank (nucleotide sequences) or Non-Redundant Protein (amino acid sequences) databases. Query and individual sequences were aligned using the BLAST 2.0 programs, available at the world wide web of the NCBI. (see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity.

The results are provided in Table 67 below.

TABLE 67 Results of search of publicly available sequence databases using SEQ ID NOS: 8804–8840 as query sequences SEQ ID NO: Description 8804 yt88d06.r1 Homo sapiens cDNA clone 231371 5′. (EST Accession No. H56522) 8805 za04c10.r1 Soares melanocyte 2NbHM Homo sapiens cDNA clone 291570 5′ (EST Accession No. W03386) 8806 Homo sapiens heat shock factor binding protein 1 HSBP1 mRNA, complete cds (GenBank Accession No. AF068754) 8807 Homo sapiens heat shock factor binding protein 1 HSBP1 mRNA, complete cds (GenBank Accession No. AF068754) 8808 Homo sapiens CGI-122 protein mRNA, complete cds (GenBank Accession No. AF151880.1) 8809 Homo sapiens CGI-122 protein mRNA, complete cds (GenBank Accession No. AF151880.1) 8810 Homo sapiens CGI-122 protein mRNA, complete cds (GenBank Accession No. AF151880.1) 8811 zn42b05.s1 Stratagene endothelial cell 937223 Homo sapiens cDNA clone 550065 3′ similar to SW: RPC9_YEAST P28000 DNA-DIRECTED RNA POLYMERASES I AND III 16 KD POLYPEPTIDE (EST Accession No. AA102570) 8812 yv31g09.r1 Soares fetal liver spleen 1NFLS Homo sapiens cDNA clone 244384 5′ similar to contains Alu repetitive element (EST Accession No. N72329) 8813 tz22h11.x1 NCI_CGAP_Ut2 Homo sapiens cDNA clone IMAGE: 2289381 3′, mRNA sequence (EST Accession No. AI635233.1) 8814 zi02h12.r1 Soares fetal liver spleen 1NFLS S1 Homo sapines cDNA clone 429671 5′ similar to contains Alu repetitive element (EST Accession No. AA011438) 8815 Human quiescin (Q6) mRNA 8816 Human Treacher Collins Syndrome 8817 Human mRNA for annexin IV (carbohydrate-binding protein p33/41) 8818 Human mRNA for TGIF protein 8819 Human MHC class I lymphocyte antigen (HLA-E) (HLA-6.2) 8820 Human HLA-E class I mRNA 8821 Human Mpv17 mRNA 8822 Human kidney cyclophilin C 8823 Human kidney cyclophilin C 8824 Human kidney cyclophilin C 8825 Human mRNA for 26S proteasome subunit p55 8826 Human gamma-interferon-inducible protein (IP-30) mRNA 8827 Human gamma-interferon-inducible protein (IP-30) mRNA 8828 Human gamma-interferon-inducible protein (IP-30) mRNA 8829 Human gamma-interferon-inducible protein (IP-30) mRNA 8830 Human gamma-interferon-inducible protein (IP-30) mRNA 8831 Human Na+/H+ exchange regulatory co-factor (NHERF) mRNA 8832 Human mRNA for mitochondrial dodecenoyl-CoA delta-isomerase 8833 Human mRNA for mitochondrial dodecenoyl-CoA delta-isomerase 8834 Human mRNA for mitochondrial dodecenoyl-CoA delta-isomerase 8835 Human mRNA for mitochondrial dodecenoyl-CoA delta-isomerase 8836 Human (clone PSK-J3) cyclin-dependent protein kinase mRNA 8837 Human serine hydroxymethyltransferase mRNA 8838 Human serine hydroxymethyltransferase mRNA 8839 Human serine hydroxymethyltransferase mRNA 8840 Human DNA damage-inducible RNA binding protein (A18hnRNP). Key: ES = EST database; GB = GenBank database

SEQ ID NO:8804 corresponds to a cDNA clone generated from an EST isolated from human pineal gland (Hillier et al. Genome Res. (1996) 6(9):807-28).

SEQ ID NO:8805 corresponds to a sequence contained within a cDNA clone derived from an EST isolated from a human melanocyte 2NbHM.

SEQ ID NOS:8806 and 8807 correspond to a sequence encoding a human heat chock factor binding protein, HSBP-1, which acts as a negative regulator of the heat shock response through its interaction with heat shock factor 1 (HSF1) (Satyal et al. Genes Dev. (1998) 12(13):1962-74). Briefly, HSF-1 responds to stress by undergoing conformational transition from an inert non-DNA binding monomer to an active trimed that exhibits rapid DNA binding and activity as a transcriptional activator. Attenuation of the inducible transcriptional response, which occurs during heat shock or upon recovery at non-stress conditions, involves dissociation of the HSF1 trimer and loss of activity. HSBP-1, a nuclear-localized, conserved, 76-amino-acid protein, contains two extended arrays of hydrophobic repeats that interact with HSF-1 heptad repeats of the active trimeric state of HSF1. During attenuation of HSF1 to the inert monomer, HSBP1 also associates with Hsp70. Through its interaction with HSF-1, HSBP1 negatively affects HSF-1 DNA-binding activity.

SEQ ID NOS:8808-8810 correspond to a gene encoding human CGI-122 protein.

SEQ ID NO:8811 corresponds to a cDNA clone generated from an EST isolated from human endothelial cells (Hillier et al. Genome Res. (1996) 6(9):807-28).

SEQ ID NOS:8812 and 8814 correspond to a cDNA clone generated from an EST isolated human fetal liver and spleen (Hillier et al. Genome Res. (1996) 6(9):807-28).

SEQ ID NO:8813 corresponds to a sequence contained within a human cDNA clone isolated from moderately-differentiated endometrial adenocarcinoma.

The gene corresponding to SEQ ID NO:8816 encodes human quiescin Q6 (Coppoch et al., 1998, Proc. Amer. Assoc. Can. Res. 39:471).

The gene corresponding to SEQ ID NO:8817 encodes a human Treacher Collins Syndrome protein. Treacher Collins Syndrome (TCS) is an autosomal dominant disorder of craniofacial development including hearing loss and cleft palate. The TCS gene (called Treacle) has been positionally cloned and has 26 exons exhibiting a low complexity serine/alanine-rich protein of about 144 kDa (Dixon et al., 1997, Genome Res. 7:223-234). Thirty-five mutations in the gene are reported from studies of individuals and families affected by Treacher Collins Syndrome (Edwards et al., 1997, Am. J. Human Genet. 60:515-524. Mutation in Treacle generally results in premature termination of the predicted protein (Nat. Genet. 12:130-136, 1996).

The gene corresponding to SEQ ID NO: 8817 encodes human annexin IV (carbohydrate-binding protein p33/41). Annexins are a family of Ca2+ and phospholipid binding proteins. Annexin IV binds to glycosaminoglycans (GAGs) in a calcium-dependent manner (Kojima et al., 1996, J. Biol. Chem. 271:7679-7685; Ishitsuka et al., 1998, J. Biol. Chem. 273:9935-9941; and Satoh et al., 1997, Biol. Pharm. Bull. 20:224-229). Annexin IV is highly expressed in various human adenocarcinoma cell lines (Satoh et al., 1997, FEBS Lett. 405:107-110), and calcium-induced relocation of annexin IV is observed in a human osteosarcoma cell line (Mohiti et al., 1995, Mol. Membr. Biol. 12:321-329).

The gene corresponding to SEQ ID NO: 8818 encodes human TGIF protein (Bertolino et al., 1995, J. Biol. Chem. 270:31178-31188).

The gene corresponding to SEQ ID NO:8819 encodes human MHC Class I lymphocyte antigen (HLA-E) (HLA-6.2), as described by Koller et al., 1988, J. Immunol. 141:897-904.

The gene corresponding to SEQ ID NO:8820 encodes human HLA-E class I mRNA, as described by Mizuno et al., 1988, J. Immunol. 140:4024-4030.

The gene corresponding to SEQ ID NO:8821 is the human glomerulosclerosis gene Mpv17, as described by Karasawa, 1993, Hum. Mol. Genet. 11:1829-1834.

The gene corresponding to any one or more of SEQ ID NOS:8822-8824 encodes a human cyclophilin C (Schneider et al., 1994, Biochemistry 33:8218-8224).

The gene corresponding to SEQ ID NO:8825 encodes human 265 proteasome subunit p55. Human 26S proteasome is a heterodimer of p44.5 and p55 (Saito et al., 1997, Gene 203:241-250) and plays a major role in the non-lysosomal degradation of intracellular proteins (Mason et al., 1998, FEBS Lett. 430:269-274). Homologues of 26S proteasome subunits are regulators of transcription and translation as described in Aravind and Ponting, 1998, Protein Sci. 7:1250-1254. Proteasomes are cylindrical particles made up of a stack of four heptameric rings (Rivett et al., 1997, Mol. Biol. Rep. 24:99-102) and 26S proteasome has stringent organization of ATPases, as described in Seeger et al., 1997, Mol. Biol. Rep. 24:83-88. In mammalian cells, the proteasome is a site for degradation of proteins, as described in Goldberg et al., 1997, Biol. Chem. 378:131-140. In addition, proteolytic processing involving 26S proteasome occurs in lesions of Alzheimer's Disease and dementia with Lewy bodies (Fergusson et al., 1996, Neurosci. Lett. 219:167-170).

The gene corresponding to any one or more of SEQ ID NOS:8826-8830 encodes human gamma-interferon-inducible protein (IP-30), Luster et al., 1988, J. Biol. Chem. 263:12036-12043.

The gene corresponding to SEQ ID NO:8831 encodes human Na⁺/H⁺ exchange regulatory co-factor (NHEFR) (Murphy et al., 1998, J. Biol. Chem. in press).

The gene corresponding to any one or more of SEQ ID NOS:8832-8835 encodes human mitochondrial dodecenoyl-CoA delta-isomerase.

The gene corresponding to SEQ ID NO:8836 encodes human (clone PSK-J3) cyclin-dependent protein kinase (Hanks, 1987, Proc. Natl. Acad. Sci. 84:388-392).

The gene corresponding to any one or more of SEQ ID NOS:8837-8839 encodes human serine hydroxymethyltransferase. Human serine hydroxymethyltransferase is a pyridoxine enzyme that is low in resting lymphocytes but increases upon antigenic or mitogenic stimuli, such as in an immune response (Trakatellis et al., 1997, Postgrad. Med. J. 73:617-622, and Trakatellis et al., 1994, Postgrad. Med. J. 70(Suppl 1):S89-S92). The catalytic function of the protein is tested as described in Kim et al., 1997, Anal. Biochem. 253:201-209.

The polynucleotide comprising SEQ ID NO:8840 corresponds to a GenBank entry having accession number AF021336, an mRNA complete coding sequence for human DNA damage-inducible RNA binding protein (A18hnRNP). The p value of 1.9⁻¹¹³ indicates an extremely high level of similarity between the sequence of SEQ ID NO: 8840 and the identified GenBank sequence. Likewise, the protein search identified a high level of similarity (p value of 2.4⁻⁶³) between the amino acid translated from the second reading frame of the polynucleotide of SEQ ID NO: 8840 and the entry HUMCIRPA_(—)1 for human mRNA for glycine-rich RNA binding protein cold-inducible RNA-binding protein (CIRP). The search of DBEST identified accession number AA166551, murine CIRP, with a p value of 5.8⁻¹¹⁵. CIRP is an 18 kD protein induced in mouse cells by mild cold stress and consists of an N-terminal RNA-binding domain and a C-terminal glycine-rich domain (Nishiyama et al., 1997, J. Cell Biol. 137(4):899). Lowering the culture temperature of BALB/3T3 cells from 37° C. to 32° C. induces CIRP expression and impairs cell growth. Suppression of CIRP with antisense oligonucleotides alleviates the impaired growth, while overexpression of CIRP impairs growth at 37° C. and prolongs the G1 phase of the cell cycle (Nishiyama et al., supra). The cloning and characterization of human CIRP was described by Nishiyama et al., 1997, Gene 204(1-2):115).

Deposit Information. The materials described in Table 68 were deposited with the American Type Culture Collection (CMCC=Chiron Master Culture Collection).

TABLE 68 Cell Lines Deposited with ATCC CMCC Cell Line Deposit Date ATCC Accession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

The deposits described herein are provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby

Example 45 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from either human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863), KM12C (Morikawa et al. Cancer Res. (1988) 48:1943-1948), or MDA-MB-231 (Brinkley et al. Cancer Res. (1980) 40:3118-3129) was used to construct a cDNA library from mRNA isolated from the cells. Sequences expressed by these cell lines were isolated and analyzed; most sequences were about 275-300 nucleotides in length. The KM12L4-A cell line is derived from the KM12C cell line. The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246). The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma.

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of 43 sequences. The remaining sequences were then used in a BLASTN vs. GenBank search; sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the GenBank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded. Second, a BLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p value less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 982 sequences listed as SEQ ID NOS:8841-9785 in the accompanying Sequence Listing and summarized in Table 69A (inserted prior to claims). Each identified polynucleotide represents sequence from at least a partial mRNA transcript.

Table 69A provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the filing date of the U.S. priority application in which the sequence was first filed; 3) the attorney docket number assigned to the priority application (for internal use); 4) the SEQ ID NO assigned to the sequence in the priority application; 5) the sequence name used as an internal identifier of the sequence; and 6) the name assigned to the clone from which the sequence was isolated. Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene.

In order to confirm the sequences of SEQ ID NOS: 8841-9785, the clones were retrieved from a library using a robotic retrieval system, and the inserts of the retrieved clones re-sequenced. These “validation” sequences are provided as SEQ ID 9786:983-9799 in the Sequence Listing, and a summary of the “validation” sequences provided in Table 69B (inserted prior to claims). Table 69B provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the sample name assigned to the “validation” sequence obtained; and 3) the name of the clone that contains the indicated “validation” sequence. “Validation” sequences can be correlated with the original sequences they validate by referring to Table 69A. Because the “validation” sequences are often longer than the original polynucleotide sequences and thus provide additional sequence information. All validation sequences can be obtained either from the corresponding clone or from a cDNA library described herein (e.g., using primers designed from the sequence provided in the sequence listing).

TABLE 69A Priority Appln Information SEQ ID SEQ ID NO: Filed Dkt NO. NO: Sequence Name Clone Name 8841 Sep. 28, 1998 1492.001 1 RTA00000617F.o.18.2 M00005513A:H01 8842 Sep. 28, 1998 1492.001 2 RTA00001075F.h.12.1 M00005434A:F11 8843 Sep. 28, 1998 1492.001 3 RTA00001076F.m.09.1 M00006946B:C08 8844 Sep. 28, 1998 1492.001 4 RTA00001075F.o.08.1 M00005628D:A10 8845 Sep. 28, 1998 1492.001 5 RTA00001064F.f.14.1 M00005465A:A07 8846 Sep. 28, 1998 1492.001 6 RTA00001075F.n.19.1 M00005614A:B07 8847 Sep. 28, 1998 1492.001 7 RTA00001075F.i.24.1 M00005453B:B06 8848 Sep. 28, 1998 1492.001 8 RTA00001075F.p.24.1 M00005721D:B03 8849 Sep. 28, 1998 1492.001 9 RTA00001075F.o.04.1 M00005621B:C09 8850 Sep. 28, 1998 1492.001 10 RTA00000616F.j.04.1 M00005412D:G07 8851 Sep. 28, 1998 1492.001 11 RTA00001064F.k.01.1 M00005708C:D11 8852 Sep. 28, 1998 1492.001 12 RTA00001064F.j.19.1 M00005657B:F11 8853 Sep. 28, 1998 1492.001 13 RTA00001065F.a.22.1 M00006920B:H07 8854 Sep. 28, 1998 1492.001 14 RTA00001076F.d.11.1 M00006623C:G07 8855 Sep. 28, 1998 1492.001 15 RTA00000615F.e.08.2 M00004872A:D07 8856 Sep. 28, 1998 1492.001 16 RTA00000617F.p.05.2 M00005515D:G02 8857 Sep. 28, 1998 1492.001 17 RTA00001076F.f.03.1 M00006668D:B10 8858 Sep. 28, 1998 1492.001 18 RTA00001064F.l.17.2 M00006582A:F12 8859 Sep. 28, 1998 1492.001 19 RTA00001076F.h.13.1 M00006745B:C05 8860 Sep. 28, 1998 1492.001 20 RTA00001075F.k.12.1 M00005482A:D08 8861 Sep. 28, 1998 1492.001 21 RTA00001076F.c.09.1 M00006594B:D05 8862 Sep. 28, 1998 1492.001 22 RTA00001076F.l.16.1 M00006919A:H12 8863 Sep. 28, 1998 1492.001 23 RTA00001076F.b.13.1 M00005825A:A10 8864 Sep. 28, 1998 1492.001 24 RTA00001065F.d.06.2 M00007078B:H04 8865 Sep. 28, 1998 1492.001 25 RTA00001075F.p.23.1 M00005721C:A12 8866 Sep. 28, 1998 1492.001 26 RTA00001075F.n.22.1 M00005616B:E11 8867 Sep. 28, 1998 1492.001 27 RTA00001075F.o.21.1 M00005648C:E10 8868 Sep. 28, 1998 1492.001 28 RTA00001065F.b.22.1 M00006968A:H05 8869 Sep. 28, 1998 1492.001 29 RTA00001075F.p.06.1 M00005698A:F12 8870 Sep. 28, 1998 1492.001 30 RTA00001076F.d.19.1 M00006630A:E05 8871 Sep. 28, 1998 1492.001 31 RTA00001075F.e.14.1 M00005375B:H03 8872 Sep. 28, 1998 1492.001 32 RTA00001065F.f.02.1 M00007186A:A12 8873 Sep. 28, 1998 1492.001 33 RTA00001064F.p.03.1 M00006814D:D09 8874 Sep. 28, 1998 1492.001 34 RTA00001076F.i.19.1 M00006813B:E04 8875 Sep. 28, 1998 1492.001 35 RTA00001077F.c.06.1 M00007157B:B04 8876 Sep. 28, 1998 1492.001 36 RTA00001064F.c.21.1 M00005366D:E12 8877 Sep. 28, 1998 1492.001 37 RTA00001065F.e.21.1 M00007177A:G07 8878 Sep. 28, 1998 1492.001 38 RTA00001076F.o.14.1 M00007038D:D01 8879 Sep. 28, 1998 1492.091 39 RTA00001064F.c.01.1 M00005327C:G08 8880 Sep. 28, 1998 1492.001 40 RTA00001064F.d.16.1 M00005397A:G08 8881 Sep. 28, 1998 1492.001 41 RTA00000615F.e.05.2 M00004870D:E05 8882 Sep. 28, 1998 1492.001 42 RTA00000616F.j.12.1 M00005413D:G12 8883 Sep. 28, 1998 1492.001 43 RTA00001075F.a.17.1 M00004852B:H08 8884 Sep. 28, 1998 1492.001 44 RTA00001076F.n.10.1 M00006989C:B01 8885 Sep. 28, 1998 1492.001 45 RTA00001075F.l.04.1 M00005505D:H08 8886 Sep. 28, 1998 1492.001 46 RTA00001075F.l.10.1 M00005509B:E10 8887 Sep. 28, 1998 1492.001 47 RTA00001075F.i.09.1 M00005444D:D01 8888 Sep. 28, 1998 1492.001 48 RTA00001075F.j.13.1 M00005464B:B08 8889 Sep. 28, 1998 1492.001 49 RTA00001076F.e.03.1 M00006635A:C01 8890 Sep. 28, 1998 1492.001 50 RTA00001076F.j.14.1 M00006837B:H12 8891 Sep. 28, 1998 1492.001 51 RTA00001075F.g.19.1 M00005418C:B09 8892 Sep. 28, 1998 1492.001 52 RTA0000I075F.m.05.1 M00005538C:H11 8893 Sep. 28, 1998 1492.001 53 RTA00001076F.p.03.1 M00007046D:E10 8894 Sep. 28, 1998 1492.001 54 RTA00001075F.h.19.1 M00005435B:F01 8895 Sep. 28, 1998 1492.001 55 RTA00001075F.h.14.1 M00005434C:E02 8896 Sep. 28, 1998 1492.001 56 RTA00001076F.l.14.1 M00006917B:C05 8897 Sep. 28, 1998 1492.001 57 RTA00001075F.h.17.1 M00005434D:H02 8898 Sep. 28, 1998 1492.001 58 RTA00001075F.f.18.1 M00005396C:H04 8899 Sep. 28, 1998 1492.001 59 RTA00001076F.l.03.1 M00006894D:A07 8900 Sep. 28, 1998 1492.001 60 RTA00001065F.d.07.2 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1998 1493.001 146 RTA00001071F.o.18.1 M00001618C:E01 9216 Sep. 28, 1998 1493.001 147 RTA00001062F.p.19.1 M00004140D:E03 9217 Sep. 28, 1998 1493.001 148 RTA00001062F.d.04.1 M00003818C:D02 9218 Sep. 28, 1998 1493.001 149 RTA00001072F.n.22.3 M00003933A:B04 9219 Sep. 28, 1998 1493.001 150 RTA00001063F.c.11.1 M00004187A:B05 9220 Sep. 28, 1998 1493.001 151 RTA00001061F.j.22.1 M00001531B:A03 9221 Sep. 28, 1998 1493.001 152 RTA00001062F.d.08.1 M00003820C:E08 9222 Sep. 28, 1998 1493.001 153 RTA00001062F.f.02.1 M00003877C:G01 9223 Sep. 28, 1998 1493.001 154 RTA00001062F.d.24.1 M00003839D:C03 9224 Sep. 28, 1998 1493.001 155 RTA00001074F.h.24.1 M00004391C:F12 9225 Sep. 28, 1998 1493.001 156 RTA00001071F.a.10.1 M00001341A:H10 9226 Sep. 28, 1998 1493.001 157 RTA00001074F.k.13.1 M00004449B:B05 9227 Sep. 28, 1998 1493.001 158 RTA00001072F.k.16.2 M00003884C:G09 9228 Sep. 28, 1998 1493.001 159 RTA00001073F.k.09.1 M00004158C:B01 9229 Sep. 28, 1998 1493.001 160 RTA00001074F.b.14.1 M00004288D:E07 9230 Sep. 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RTA00001078F.d.17.1 M00008028D:B01 9757 Oct. 8, 1998 1495.001 253 RTA00001067F.d.07.1 M00022203B:A05 9758 Oct. 8, 1998 1495.001 254 RTA00001068F.e.04.1 M00022903D:H02 9759 Oct. 8, 1998 1495.001 255 RTA00001068F.a.06.1 M00022682A:F10 9760 Oct. 8, 1998 1495.001 256 RTA00001078F.e.10.1 M00008054C:E07 9761 Oct. 8, 1998 1495.001 257 RTA00001079F.b.11.1 M00022056B:G12 9762 Oct. 8, 1998 1495.001 258 RTA00001066F.h.11.1 M00021676B:B12 9763 Oct. 8, 1998 1495.001 259 RTA00001079F.d.01.1 M00022084B:C03 9764 Oct. 8, 1998 1495.001 260 RTA00001067F.g.14.1 M00022363C:D03 9765 Oct. 8, 1998 1495.001 261 RTA00001066F.g.06.1 M00021625B:G07 9766 Oct. 8, 1998 1495.001 262 RTA00001081F.j.09.2 M00022893D:C06 9767 Oct. 8, 1998 1495.001 263 RTA00001068F.e.19.1 M00022963A:E07 9768 Oct. 8, 1998 1495.001 264 RTA00001079F.l.21.1 M00022282A:A11 9769 Oct. 8, 1998 1495.001 265 RTA00001078F.h.09.1 M00021624B:E11 9770 Oct. 8, 1998 1495.001 266 RTA00001078F.d.16.1 M00008027D:H09 9771 Oct. 8, 1998 1495.001 267 RTA00001079F.g.22.2 M00022167B:H02 9772 Oct. 8, 1998 1495.001 268 RTA00001066F.e.15.1 M00008075D:B01 9773 Oct. 8, 1998 1495.001 269 RTA00001080F.g.16.1 M00022538D:B02 9774 Oct. 8, 1998 1495.001 270 RTA00001080F.b.07.1 M00022447A:H06 9775 Oct. 8, 1998 1495.001 271 RTA00001078F.n.21.2 M00021958A:A03 9776 Oct. 8, 1998 1495.001 272 RTA00001078F.b.12.1 M00007998C:B04 9777 Oct. 8, 1998 1495.001 273 RTA00001066F.p.01.2 M00022099C:A10 9778 Oct. 8, 1998 1495.001 274 RTA00001066F.o.22.1 M00022095C:F03 9779 Oct. 8, 1998 1495.001 275 RTA00001080F.i.19.1 M00022568B:D03 9780 Oct. 8, 1998 1495.001 276 RTA00001079F.g.01.1 M00022138C:B07 9781 Oct. 8, 1998 1495.001 277 RTA00001079F.e.02.1 M00022102D:A10 9782 Oct. 8, 1998 1495.001 278 RTA00001079F.k.01.1 M00022233C:D11 9783 Oct. 8, 1998 1495.001 279 RTA00001079F.o.11.1 M00022386D:C04 9784 Oct. 8, 1998 1495.001 280 RTA00001068F.d.02.1 M00022834A:H02 9785 Oct. 8, 1998 1495.001 281 RTA00001078F.a.07.1 M00007939A:F06 9786 Oct. 8, 1998 1495.001 282 RTA00001081F.b.20.1 M00022743C:G06 9787 Oct. 8, 1998 1495.001 283 RTA00001067F.f.20.1 M00022273A:B03 9788 Oct. 8, 1998 1495.001 284 RTA00001079F.c.06.1 M00022072D:E12 9789 Oct. 8, 1998 1495.001 285 RTA00001068F.b.24.1 M00022768A:A10 9790 Oct. 8, 1998 1495.001 286 RTA00001080F.o.08.1 M00022691A:G01 9791 Oct. 8, 1998 1495.001 287 RTA00001078F.j.10.2 M00021687C:A04 9792 Oct. 8, 1998 1495.001 288 RTA00001080F.b.03.1 M00022444B:C04 9793 Oct. 8, 1998 1495.001 289 RTA00001067F.e.13.1 M00022240C:B03 9794 Oct. 8, 1998 1495.001 290 RTA00001081F.h.05.1 M00022856A:B09 9795 Oct. 8, 1998 1495.001 291 RTA00001067F.f.01.1 M00022252C:A04 9796 Oct. 8, 1998 1495.001 292 RTA00001080F.g.23.1 M00022542A:B06 9797 Oct. 8, 1998 1495.001 293 RTA00001080F.h.16.1 M00022548A:F02 9798 Oct. 8, 1998 1495.001 294 RTA00001080F.f.15.1 M00022517C:B01 9799 Oct. 8, 1998 1495.001 295 RTA00001080F.f.06.1 M00022513C:E10 9800 Oct. 8, 1998 1495.001 296 RTA00001081F.a.04.2 M00022716A:C01 9801 Oct. 8, 1998 1495.001 297 RTA00001078F.p.16.2 M00022001B:H10 9802 Oct. 8, 1998 1495.001 298 RTA00001081F.b.03.1 M00022734C:A03 9803 Oct. 8, 1998 1495.001 299 RTA00001080F.a.21.1 M00022441B:A06 9804 Oct. 8, 1998 1495.001 300 RTA00001079F.f.05.1 M00022127C:E01 9805 Oct. 8, 1998 1495.001 301 RTA00001080F.n.23.1 M00022681D:H10 9806 Oct. 8, 1998 1495.001 302 RTA00001078F.c.18.1 M00008016C:E06 9807 Oct. 8, 1998 1495.001 303 RTA00001068F.a.11.1 M00022697A:C08 9808 Oct. 8, 1998 1495.001 304 RTA00001068F.g.09.1 M00023095C:A09 9809 Oct. 8, 1998 1495.001 305 RTA00001068F.a.22.1 M00022709A:C01 9810 Oct. 8, 1998 1495.001 306 RTA00001079F.h.09.2 M00022176D:F05 9811 Oct. 8, 1998 1495.001 307 RTA00001079F.h.01.2 M00022169A:E11 9812 Oct. 8, 1998 1495.001 308 RTA00001078F.g.07.1 M00008097C:E04 9813 Oct. 8, 1998 1495.001 309 RTA00001078F.m.08.2 M00021908B:F03 9814 Oct. 8, 1998 1495.001 310 RTA00001080F.a.03.1 M00022417B:C01 9815 Oct. 8, 1998 1495.001 311 RTA00001079F.o.06.1 M00022384B:E06 9816 Oct. 8, 1998 1495.001 312 RTA00001079F.p.06.1 M00022401C:G07 9817 Oct. 8, 1998 1495.001 313 RTA00001078F.p.18.2 M00022001D:E06 9818 Oct. 8, 1998 1495.001 314 RTA00001068F.a.17.1 M00022705B:F08 9819 Oct. 8, 1998 1495.001 315 RTA00001078F.a.10.1 M00007948C:G01 9820 Oct. 8, 1998 1495.001 316 RTA00001079F.h.20.2 M00022184D:H07 9821 Oct. 8, 1998 1495.001 317 RTA00001081F.n.03.1 M00022986B:C02 9822 Oct. 8, 1998 1495.001 318 RTA00001080F.c.04.1 M00022460D:C07

Example 46 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS:8841-9919 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in either the GenBank (nucleotide sequences) or Non-Redundant Protein (amino acid sequences) databases. Query and individual sequences were aligned using the BLAST 2.0 programs, available over the world wide web. (see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above.

Tables 70A and 70B (inserted before the claims) provide the alignment summaries having a p value of 1×10⁻² or less indicating substantial homology between the sequences of the present invention and those of the indicated public databases. Table 70A provides the SEQ ID NO of the query sequence, the accession number of the GenBank database entry of the homologous sequence, and the p value of the alignment. Table 70A provides the SEQ ID NO of the query sequence, the accession number of the Non-Redundant Protein database entry of the homologous sequence, and the p value of the alignment. The alignments provided in Tables 70A and 70B are the best available alignment to a DNA or amino acid sequence at a time just prior to filing of the present specification. The activity of the polypeptide encoded by the SEQ ID NOS listed in Tables 70A and 70B can be extrapolated to be substantially the same or substantially similar to the activity of the reported nearest neighbor or closely related sequence. The accession number of the nearest neighbor is reported, providing a publicly available reference to the activities and functions exhibited by the nearest neighbor. The public information regarding the activities and functions of each of the nearest neighbor sequences is incorporated by reference in this application. Also incorporated by reference is all publicly available information regarding the sequence, as well as the putative and actual activities and functions of the nearest neighbor sequences listed in Table 70 and their related sequences. The search program and database used for the alignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of the corresponding polynucleotide. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of the corresponding polynucleotides.

Example 47 Identification of Contiguous Sequences Having a Polynucleotide of the Invention

The novel polynucleotides were used to screen publicly available and proprietary databases to determine if any of the polynucleotides of SEQ ID NOS:8841-9785 would facilitate identification of a contiguous sequence, e.g., the polynucleotides would provide sequence that would result in 5′ extension of another DNA sequence, resulting in production of a longer contiguous sequence composed of the provided polynucleotide and the other DNA sequence(s). Contiging was performed using the Gelmerge application (default settings) of GCG from the Univ. of Wisconsin.

Using these parameters, 83 contiged sequences were generated. These contiged sequences are provided as SEQ ID NOS:9800-9882 (see Table 69C). Table 69C provides the SEQ ID NO of the contig sequence, the name of the sequence used to create the contig, and the accession number of the publicly available tentative human consensus (THC) sequence used with the sequence of the corresponding sequence name to provide the contig. The sequence name of Table 69C can be correlated with the SEQ ID NO: of the polynucleotide used to generate the contig by referring to Tables 69A and 69B.

The contiged sequences (SEQ ID NOS: 9800-9882) represent longer sequences that encompass another of the polynucleotide sequence of the invention. The contiged sequences were then translated in all three reading frames to determine the best alignment with individual sequences using the BLAST programs as described above. The sequences were masked using the XBLAST program for masking low complexity as described above. As described in more detail below, several of the contiged sequences were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (see Example 4 and Table 71 below). Thus the invention encompasses fragments, fusions, and variants of such polynucleotides that retain biological activity associated with the protein family and/or functional domain identified herein.

Example 48 Members of Protein Families

SEQ ID NOS:8841-9919 were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein family (and thus represent members of these protein families) and/or comprising a known functional domain. Table 71 (inserted before claims) provides the SEQ ID NO: of the query sequence, a brief description of the profile hit, the position of the query sequence within the individual sequence (indicated as “start” and “stop”), and the orientation (Direction, “Dir”) of the query sequence with respect to the individual sequence, where forward (for) indicates that the alignment is in the same direction (left to right) as the sequence provided in the Sequence Listing and reverse (rev) indicates that the alignment is with a sequence complementary to the sequence provided in the Sequence Listing.

Some polynucleotides exhibited multiple profile hits where the query sequence contains overlapping profile regions, and/or where the sequence contains two different functional domains. Each of the profile hits of Table 71 are described in more detail below. The acronyms for the profiles (provided in parentheses) are those used to identify the profile in the Pfam and Prosite databases. The public information available on the Pfam and Prosite databases regarding the various profiles, including but not limited to the activities, function, and consensus sequences of various proteins families and protein domains, is incorporated herein by reference.

TABLE 71 SEQ ID NO: Profilename Start Stop Direction 8937 Kazal 25 243 for 9067 helicase_C 212 389 for 9082 EFhand 275 310 for 9290 SH3 44 226 for 9313 Zincfing_C2H2 211 273 for 9345 WD_domain 80 178 for 9352 Zincfing_C2H2 147 209 for 9363 PDZ 168 395 for 9367 ras 18 395 for 9385 ANK 311 393 for 9387 Ets_Nterm 7 237 for 9446 WW_domain 120 209 for 9475 protkinase 47 400 for 9475 mkk 41 394 for 9476 trypsin 147 381 for 9480 Zincfing_C2H2 122 184 for 9533 Zincfing_CCHC 135 185 for 9561 WD_domain 18 116 for 9645 Zincfing_C3HC4 263 406 for 9758 BZIP 51 224 for 9759 Zincfing_C2H2 125 187 for 9765 FKH 9 230 for 9811 Zincfing_C2H2 202 264 for 9813 Zincfing_CCHC 262 309 for 9820 PDZ 241 468 for 9832 mkk 0 708 for 9832 protkinase 121 711 for 9835 trypsin 202 760 for 9824 trypsin 202 760 for 9858 WD_domain 18 116 for 9868 pr55 24 1293 for 9875 ATPases 74 616 for 9876 Zincfing_C2H2 122 184 for 9893 14_3_3 63 619 for 9898 helicase_C 212 448 for 9898 ATPases 59 442 for 9903 Zincfing_C2H2 211 273 for 9906 Zincfing_C2H2 125 187 for 9912 ATPases 808 1284 for 9918 protkinase 309 1022 rev 9918 neur_chan 12 508 rev 9918 Zincfing_CCHC 262 309 for 9918 Zincfing_C3HC4 557 679 for

14-3-3 Family (14_(—)3_(—)3; Pfam Pfam Accession No. PF00244). One SEQ ID NO corresponds to a sequence encoding a 14-3-3 protein family member. The 14-3-3 protein family includes a group of closely related acidic homodimeric proteins of about 30 kD first identified as very abundant in mammalian brain tissues and located preferentially in neurons (Aitken et al. Trends Biochem. Sci. (1995) 20:95-97; Morrison Science (1994) 266:56-57; and Xiao et al. Nature (1995) 376:188-191). The 14-3-3 proteins have multiple biological activities, including a key role in signal transduction pathways and the cell cycle. 14-3-3 proteins interact with kinases (e.g., PKC or Raf-1), and can also function as protein-kinase dependent activators of tyrosine and tryptophan hydroxylases. The 14-3-3 protein sequences are extremely well conserved, and include two highly conserved regions: the first is a peptide of 11 residues located in the N-terminal section; the second, a 20 amino acid region located in the C-terminal section.

Ank Repeats (ANK; Pfam Accession No. PF0023). One SEQ ID NO represents a polynucleotide encoding an Ank repeat-containing protein. The ankyrin motif is a 33 amino acid sequence named after the protein ankyrin which has 24 tandem 33-amino-acid motifs. Ank repeats were originally identified in the cell-cycle-control protein cdc10 (Breeden et al., Nature (1987) 329:651). Proteins containing ankyrin repeats include ankyrin, myotropin, I-kappaB proteins, cell cycle protein cdc10, the Notch receptor (Matsuno et al., Development (1997) 124(21):4265); G9a (or BAT8) of the class III region of the major histocompatibility complex (Biochem J. 290:811-818, 1993), FABP, GABP, 53BP2, Lin12, glp-1, SW14, and SW16. The functions of the ankyrin repeats are compatible with a role in protein-protein interactions (Bork, Proteins (1993) 17(4):363; Lambert and Bennet, Eur. J. Biochem. (1993) 211:1; Kerr et al., Current Op. Cell Biol. (1992) 4:496; Bennet et al., J. Biol. Chem. (1980) 255:6424).

ATPases Associated with Various Cellular Activities (ATPases; Pfam Accession No. PF0004). Some SEQ ID NOS correspond to a sequence that encodes a member of a family of ATPases Associated with diverse cellular Activities (AAA). The AAA protein family is composed of a large number of ATPases that share a conserved region of about 220 amino acids containing an ATP-binding site (Froehlich et al, J. Cell Biol. (1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieri et al., BioEssays (1995) 17:639). The AAA domain, which can be present in one or two copies, acts as an ATP-dependent protein clamp (Confalonieri et al. (1995) BioEssays 17:639) and contains a highly conserved region located in the central part of the domain.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP; Pfam Accession No. PF00170). One SEQ ID NO represents a polynucleotide encoding a novel member of the family of basic region plus leucine zipper transcription factors. The bZIP superfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcription factors encompasses proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper required for dimerization.

EF Hand (Efhand; Pfam Accession No. PF00036). One SEQ ID NO corresponds to a polynucleotide encoding a member of the EF-hand protein family, a calcium binding domain shared by many calcium-binding proteins belonging to the same evolutionary family (Kawasaki et al., Protein. Prof. (1995) 2:305-490). The domain is a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain, with a calcium ion coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).

Ets Domain (Ets_Nterm; Pfam Accession No. PF110178). One SEQ ID NO, and thus the sequence it validates, represents a polynucleotide encoding a polypeptide with N-terminal homology in ETS domain. Proteins of this family contain a conserved domain, the “ETS-domain,” that is involved in DNA binding. The domain appears to recognize purine-rich sequences; it is about 85 to 90 amino acids in length, and is rich in aromatic and positively charged residues (Wasylyk, et al., Eur. J. Biochem. (1993) 211:718). The ets gene family encodes a novel class of DNA-binding proteins, each of which binds a specific DNA sequence and comprises an ets domain that specifically interacts with sequences containing the common core tri-nucleotide sequence GGA. In addition to an ets domain, native ets proteins comprise other sequences which can modulate the biological specificity of the protein. Ets genes and proteins are involved in a variety of essential biological processes including cell growth, differentiation and development, and three members are implicated in oncogenic process.

(FKH; Pfam Accession No. PF00250). One SEQ. ID NO corresponds to a gene encoding a polypeptide comprising a forkhead domain. The forkhead domain (also known as a “winged helix”) is present in a family of eukaryotic transcription factors, and is a conserved domain of about 100 amino acid residues that is involved in DNA-binding (Weigel et al. Cell (1990) 63:455-456; Clark et al. Nature (1993) 364:412-420). Mammalian genes that comprise a forkhead domain include those encoding: 1) transcriptional activators (e.g., HNF-3-alpha, -beta, and -gamma proteins, which interact with the cis-acting regulatory regions of a number of liver genes); 2) interleukin-enhancer binding factor (ILF), which binds to purine-rich NFAT-like motifs in the HIV-1 LTR and the interleukin-2 promoter and is involved in both positive and negative regulation of important viral and cellular promoter elements; 3) transcription factor BF-1, which plays an important role in the establishment of the regional subdivision of the developing-brain and in the development of the telencephalon; 4) human HTLF, which binds to the purine-rich region in human T-cell leukemia virus long terminal repeat (HTLV-I LTR); 5) transcription factors FREAC-1 (FKHL5, HFH-8), FREAC-2 (FKHL6), FREAC-3 (FKHL7, FKH-1), FREAC-4 (FKHL8), FREAC-5 (FKHL9, FKH-2, HFH-6), FREAC-6 (FKHL10, HFH-5), FREAC-7 (FKHL11), FREAC-8 (FKHL12, HFH-7), FKH-3, FKH-4, FKH-5, HFH-1 and HFH-4; 6) human AFX1 which is involved in a chromosomal translocation that causes acute leukemia; and 7) human FKHR which is involved in a chromosomal translocation that causes rhabdomyosarcoma. The fork domain is highly conserved, and is detected by two consensus patterns: the first corresponding to the N-terminal section of the domain; the second corresponding to a heptapeptide located in the central section of the domain.

Helicases conserved C-terminal domain (helicase C; Pfam Accession No. PF00271). Some SEQ ID NOS represent polynucleotides encoding novel members of the DEAD/H helicase family. The DEAD box family comprises a number of eukaryotic and prokaryotic proteins involved in ATP-dependent, nucleic-acid unwinding. All DEAD box family members of the above proteins share a number of conserved sequence motifs, some of which are specific to the DEAD family while others are shared by other ATP-binding proteins or by proteins belonging to the helicases ‘superfamily’ (Hodgman, Nature (1988) 333:22 and Nature (1988) 333:578; see worldwide web site at expasy.ch/www/linder/-HELICASES_TEXT.html). One of these motifs, called the ‘D-E-A-D-box’, represents a special version of the B motif of ATP-binding proteins. Some other proteins belong to a subfamily which have His instead of the second Asp and are thus said to be ‘D-E-A-H-box’ proteins (Wassarman D. A., et al., Nature (1991) 349:463; Harosh I., et al., Nucleic Acids Res. (1991) 19:6331; Koonin E. V., et al., J. Gen. Virol. (1992) 73:989).

Kazal serine protease inhibitors family signature (Kazal; Pfam Accession No. PF00050). One SEQ ID NO corresponds to a polynucleotide of a gene encoding a serine protease inhibitor of the Kazal inhibitor family (Laskowski et al. Annu. Rev. Biochem. (1980) 49:593-626). The basic structure of Kazal serine protease inhibitors such a type of inhibitor is described at Pfam Accession No. PF00050. Exemplary proteins known to belong to this family include: pancreatic secretory trypsin inhibitor (PSTI), whose physiological function is to prevent the trypsin-catalyzed premature activation of zymogens within the pancreas; mammalian seminal acrosin inhibitors; canidae and felidae submandibular gland double-headed protease inhibitors, which contain two Kazal-type domains, the first one inhibits trypsin and the second one elastase; a mouse prostatic secretory glycoprotein, induced by androgens, and which exhibits anti-trypsin activity; avian ovomucoids; chicken ovoinhibitor; and the leech trypsin inhibitor Bdellin B-3.

MAP kinase kinase (mkk). Some SEQ ID NOS represent members of the MAP kinase kinase (mkk) family. MAP kinases (MAPK) are involved in signal transduction, and are important in cell cycle and cell growth controls. The MAP kinase kinases (MAPKK) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKKs are essential transducers through which signals must pass before reaching the nucleus. For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishida et al., Trends Biochem Sci (1993) 18:128-31; Ruderman Curr Opin Cell Biol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55; Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal (1996) 8:533-44.

Neurotransmitter-Gated Ion-Channel (neur_chan, Pfam Accession No. PF00065). One SEQ ID NO corresponds to a sequence encoding a neurotransmitter-gated ion channel. Neurotransmitter-gated ion-channels, which provide the molecular basis for rapid signal transmission at chemical synapses, are post-synaptic oligomeric transmembrane complexes that transiently form a ionic channel upon the binding of a specific neurotransmitter. Five types of neurotransmitter-gated receptors are known: 1) nicotinic acetylcholine receptor (AchR); 2) glycine receptor; 3) gamma-aminobutyric-acid (GABA) receptor; 4) serotonin 5HT3 receptor; and 5) glutamate receptor. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related, and are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions that form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence.

PDZ Domain (PDZ; Pfam Accession No. PF00595.) Some SEQ ID NOS correspond to a gene comprising a PDZ domain (also known as DHR or GLGF domain). PDZ domains comprise 80-100 residue repeats, several of which interact with the C-terminal tetrapeptide motifs X-Ser/Thr-X-Val-COO- of ion channels and/or receptors, and are found in mammalian proteins as well as in bacteria, yeast, and plants (Pontig et al. Protein Sci (1997) 6(2):464-8). Proteins comprising one or more PDZ domains are found in diverse membrane-associated proteins, including members of the MAGUK family of guanylate kinase homologues, several protein phosphatases and kinases, neuronal nitric oxide synthase, and several dystrophin-associated proteins, collectively known as syntrophins (Ponting et al. Bioessays (1997) 19(6):469-79). Many PDZ domain-containing proteins are localised to highly specialised submembranous sites, suggesting their participation in cellular junction formation, receptor or channel clustering, and intracellular signalling events. For example, PDZ domains of several MAGUKs interact with the C-terminal polypeptides of a subset of NMDA receptor subunits and/or with Shaker-type K+ channels. Other PDZ domains have been shown to bind similar ligands of other transmembrane receptors. In cell junction-associated proteins, the PDZ mediates the clustering of membrane ion channels by binding to their C-terminus. The X-ray crystallographic structure of some proteins comrpising PDZ domains have been solved (see, e.g., Doyle et al. Cell (1996) 85(7):1067-76).

Protein phosphatase 2A regulatory subunit PR55 signatures (PR55; Pfam Accession No. PF01240). One SEQ ID NO corresponds to a gene encoding a protine phosphatase 2A regulatory subunit. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in many aspects of cellular function including the regulation of metabolic enzymes and proteins involved in signal transduction. PP2A is a trimeric enzyme that consists of a core composed of a catalytic subunit associated with a 65 Kd regulatory subunit (PR65), also called subunit A; this complex then associates with a third variable subunit (subunit B), which confers distinct properties to the holoenzyme (Mayer et al. Trends Cell Biol. (1994) 4:287-291). One of the forms of the variable subunit is a 55 Kd protein (PR55) which is highly conserved in mammals (where three isoforms are known to exist). This subunit may perform a substrate recognition function or be responsible for targeting the enzyme complex to the appropriate subcellular compartment.

Protein Kinase (protkinase; Pfam Accession No. PF00069). Some SEQ ID NOS represent polynucleotides encoding protein kinases, which catalyze phosphorylation of proteins in a variety of pathways, and are implicated in cancer. Eukaryotic protein kinases (Hanks, et al., FASEB J. (1995) 9:576; Hunter, Meth. Enzymol. (1991) 200:3; Hanks, et al., Meth. Enzymol. (1991) 200:38; Hanks, Curr. Opin. Struct. Biol. (1991) 1:369; Hanks et al., Science (1988) 241:42) belong to a very extensive family of proteins that share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. The first region, located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. The second region, located in the central part of the catalytic domain, contains a conserved an aspartic acid residue that is important for the catalytic activity of the enzyme (Knighton, et al., Science (1991) 253:407).

The protein kinase profile includes two signature patterns for this second region: one specific for serine/threonine kinases and the other for tyrosine kinases. A third profile is based on the alignment in (Hanks, et al., FASEB J. (1995) 9:576) and covers the entire catalytic domain.

Ras family proteins (ras; Pfam Accession No. PF00071). One SEQ ID NO represents polynucleotides encoding the ras family of small GTP/GDP-binding proteins (Valencia et al., 1991, Biochemistry 30:4637-4648). Ras family members generally require a specific guanine nucleotide exchange factor (GEF) and a specific GTPase activating protein (GAP) as stimulators of overall GTPase activity. Among ras-related proteins, the highest degree of sequence conservation is found in four regions that are directly involved in guanine nucleotide binding. The first two constitute most of the phosphate and Mg2+ binding site (PM site) and are located in the first half of the G-domain. The other two regions are involved in guanosine binding and are located in the C-terminal half of the molecule. Motifs and conserved structural features of the ras-related proteins are described in Valencia et al., 1991, Biochemistry 30:4637-4648.

Src homology domain 3 (SH3; Pfam Accession No. PF00018). One SEQ ID NO corresponds to a gene comprising a Src homology domain. The Src homology 3 (SH3) domain is a small protein domain of about 60 amino acid residues first identified as a conserved sequence in the non-catalytic part of several cytoplasmic protein tyrosine kinases (e.g. Src, Abl, Lck) (Mayer et al. Nature (1988) 332:272-275). Since then, it has been found in a great variety of other intracellular or membrane-associated proteins (Musacchio et al. FEBS Lett. (1992) 307:55-61; Pawson et al. Curr. Biol. (1993) 3:434-442; Mayer et al. Trends Cell Biol. (1993) 3:8-13; Pawson Nature (1995) 373:573-580). The SH3 domain has a characteristic fold which consists of five or six beta-strands arranged as two tightly packed anti-parallel beta sheets. The linker regions may contain short helices (Kuriyan et al. Curr. Opin. Struct. Biol. (1993) 3:828-837). The SH3 domain is thought to mediate assembly of specific protein complexes via binding to proline-rich peptides (Morton et al. Curr. Biol. (1994) 4:615-617). In general SH3 domains are found as single copies in a given protein, but there a significant number of proteins comprise two SH3 domains and a few comprise 3 or 4 copies. The profile to detect SH3 domains is based on a structural alignment consisting of 5 gap-free blocks and 4 linker regions totaling 62 match positions.

Trypsin (trypsin; Pfam Accession No. PF00089). Some SEQ ID NOS correspond to novel serine proteases of the trypsin family. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved (Brenner Nature (1988) 334:528).

WD Domain, G-Beta Repeats (WD_domain; Pfam Accession No. PF00400). Some SEQ ID NOS represent a members of the WD domain/G-beta repeat family. Beta-transducin (G-beta) is one of the three subunits (alpha, beta, and gamma) of the guanine nucleotide-binding proteins (G proteins) which act as intermediaries in the transduction of signals generated by transmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds to and hydrolyzes GTP; the beta and gamma subunits are required for the replacement of GDP by GTP as well as for membrane anchoring and receptor recognition. In higher eukaryotes, G-beta exists as a small multigene family of highly conserved proteins of about 340 amino acid residues. Structurally, G-beta has eight tandem repeats of about 40 residues, each containing a central Trp-Asp motif (this type of repeat is sometimes called a WD-40 repeat).

WW/rsp5/WWP domain signature and profile (WW domain; Pfam Accession No. PF00397). One SEQ ID NO corresponds to a gene encoding a protein comprising a WW domain. The WW domain (Bork et al. Trends Biochem. Sci. (1994) 19:531-533; Andre et al. Biochem. Biophys. Res. Commun. (1994) 205:1201-1205; Hofmann et al. FEBS Lett. (1995) 358:153-157; Sudol et al. FEBS Lett. (1995) 369:67-71 (also known as rsp5 or WWP) was discovered as a short conserved region in a number of unrelated proteins, among them dystrophin, the gene responsible for Duchenne muscular dystrophy. The domain, which spans about 35 residues, is repeated up to 4 times in some proteins. It has been shown (Chen et al. Proc. Natl. Acad. Sci. U.S.A. (1995) 92:7819-7823) to bind proteins with particular proline-motifs, [AP]-P-P-[AP]-Y, and thus resembles somewhat SH3 domains. The WW domain conatins beta-strands grouped around four conserved aromatic positions, generally tryptophan. The name WW or WWP derives from the presence of two tryptophane as well as a conserved proline. The WW domain is frequently associated with other domains typical for proteins in signal transduction processes.

Zinc Finger, C2H2 Type (Zincfing_C2H2; Pfam Accession No. PF00096). Several sequences corresponded to polynucleotides encoding members of the C2H2 type zinc finger protein family, which contain zinc finger domains that facilitate nucleic acid binding (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99). In addition to the conserved zinc ligand residues, a number of other positions are also important for the structural integrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved position, which is generally an aromatic or aliphatic residue, is located four residues after the second cysteine.

Zinc finger, C3HC4 type (RING finger), signature (Zincfing_C3H4; Pfam Accession No. PF00097). Some SEQ ID NOS represent polynucleotides encoding a polypeptide having a C3HC4 type zinc finger signature. A number of eukaryotic and viral proteins contain this signature, which is primarily a conserved cysteine-rich domain of 40 to 60 residues (Borden K. L. B., et al., Curr. Opin. Struct. Biol. (1996) 6:395) that binds two atoms of zinc, and is probably involved in mediating protein-protein interactions. The 3D structure of the zinc ligation system is unique to the RING domain and is referred to as the “cross-brace” motif.

Zinc finger CCHC type (Zincfing_CCHC; Pfam Accession No. PF00098). Some SEQ ID NOS correspond to genes encoding a member of the family of CCHC zinc fingers. Because the prototype CCHC type zinc finger structure is from an HIV protein, this domain is also referred to as a retrovrial-type zinc finger domain. The family also contains proteins involved in eukaryotic gene regulation, such as C. elegans GLH-1. The structure is an 18-residue zinc finger; no examples of indels in the alignment. The motif that defines a CCHC type zinc finger domain is: C-X2-C-X4-H-X4-C (Summers J Cell Biochem 1991 January; 45(1):41-8). The domain is found in, for example, HIV-1 nucleocapsid protein, Moloney murine leukemia virus nucleocapsid protine NCp10 (De Rocquigny et al. Nucleic Acids Res. (1993) 21:823-9), and myelin transcription factor 1 (Myt1) (Kim et al. J. Neurosci. Res. (1997) 50:272-90).

Example 49 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 72 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 72 Description of cDNA Libraries Number of Clones Library in (lib #) Description Library 1 Human Colon Cell Line Km12 L4: High Metastatic 308731 Potential (derived from Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic 284771 Potential 3 Human Breast Cancer Cell Line MDA-MB-231: High 326937 Metastatic Potential; micro-mets in lung 4 Human Breast Cancer Cell Line MCF7: Non 318979 Metastatic 8 Human Lung Cancer Cell Line MV-522: High 223620 Metastatic Potential 9 Human Lung Cancer Cell Line UCP-3: Low 312503 Metastatic Potential 12 Human microvascular endothelial cells (HMVEC) - 41938 UNTREATED (PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells (HMVEC) - 42100 bFGF TREATED (PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells (HMVEC) - 42825 VEGF TREATED (PCR (OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTED 282722 PCR (OligodT) cDNA library) 16 Colon Tumor - UC#2 Patient (MICRODISSECTED 298831 PCR (OligodT) cDNA library) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467 (MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED 36216 PCR (OligodT) cDNA library) 19 Colon Tumor - UC#3 Patient (MICRODISSECTED 41388 PCR (OligodT) cDNA library) 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 (MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived from normal prostate 164801 epithelium 22 WOca Cells derived from Gleason Grade 4 prostate 162088 cancer epithelium 23 Normal Lung Epithelium of Patient #1006 306198 (MICRODISSECTED PCR (OligodT) cDNA library) 24 Primary tumor, Large Cell Carcinoma of Patient 309349 #1006 (MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4, KM12C, and MDA-MB-231 cell lines are described in example 45 above. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cell lines were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974).

Examples 50-54 Differential Expression of Polynucleotides of the Invention

A number of polynucleotide sequences have been identified that are differentially expressed between, for example, cells derived, from high metastatic potential cancer tissue and low metastatic cancer cells, and between cells derived from metastatic cancer tissue and normal tissue. Evaluation of the levels of expression of the genes corresponding to these sequences can be valuable in diagnosis, prognosis, and/or treatment (e.g., to facilitate rationale design of therapy, monitoring during and after therapy, etc.). Moreover, the genes corresponding to differentially expressed sequences described herein can be therapeutic targets due to their involvement in regulation (e.g., inhibition or promotion) of development of, for example, the metastatic phenotype. For example, sequences that correspond to genes that are increased in expression in high metastatic potential cells relative to normal or non-metastatic tumor cells may encode genes or regulatory sequences involved in processes such as angiogenesis, differentiation, cell replication, and metastasis.

Detection of the relative expression levels of differentially expressed polynucleotides described herein can provide valuable information to guide the clinician in the choice of therapy. For example, a patient sample exhibiting an expression level of one or more of these polynucleotides that corresponds to a gene that is increased in expression in metastatic or high metastatic potential cells may warrant more aggressive treatment for the patient. In contrast, detection of expression levels of a polynucleotide sequence that corresponds to expression levels associated with that of low metastatic potential cells may warrant a more positive prognosis than the gross pathology would suggest.

A number of polynucleotide sequences of the present invention are differentially expressed between human microvascular endothelial cells (HMVEC) that have been treated with growth factors relative to untreated HMVEC. Sequences that are differentially expressed between growth factor-treated HMVEC and untreated HMVEC can represent sequences encoding gene products involved in angiogenesis, metastasis (cell migration), and other development and oncogenic processes. For example, sequences that are more highly expressed in HMVEC treated with growth factors (such as bFGF or VEGF) relative to untreated HMVEC can serve as drug targets for chemotherapeutics, e.g., decreasing expression of such up-regulated genes or inhibiting the activity of the encoded gene product would serve to inhibit tumor cell angiogenesis. Detection of expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The differential expression of the polynucleotides described herein can thus be used as, for example, diagnostic markers, prognostic markers, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers. The following examples provide relative expression levels of polynucleotides from specified cell lines and patient tissue samples.

Example 50 High Metastatic Potential Breast Cancer Versus Low Metastatic Breast Cancer Cells

The tables bellow summarize the data for polynucleotides that represent genes differentially expressed between high metastatic potential and low metastatic potential breast cancer cells.

TABLE 73 High metastatic potential breast (lib3) > low metastatic potential breast cancer cells (lib4) SEQ ID NO: Lib 3 Clones Lib4 Clones Lib3/Lib4 9621 13 0 12.68 9618 9 0 8.78 9596 8 0 7.81 9619 7 0 6.83 9531 7 0 6.83 9526 7 0 6.83 9756 6 0 5.85

TABLE 74 Low metastatic potential breast (lib4) > high metastatic potential breast cancer cells (lib3) SEQ ID NO: Lib 3 Clones Lib4 Clones Lib4/Lib3 9398 0 340 348.48 9496 0 64 65.6 9501 0 57 58.42 9487 0 43 44.07 9387 0 41 42.02 9488 0 40 41 9432 4 115 29.47 9494 0 28 28.7 9486 0 21 21.52 9476 3 61 20.84 9373 1 17 17.42 9389 0 17 17.42 9490 3 50 17.08 9429 0 16 16.4 8950 0 16 16.4 9497 0 16 16.4 9464 0 16 16.4 9477 0 13 13.32 9376 0 12 12.3 9493 1 11 11.27 9402 1 11 11.27 9427 1 11 11.27 9449 1 11 11.27 9430 0 10 10.25 9481 0 10 10.25 9372 1 10 10.25 9463 0 9 9.22 9431 0 8 8.2 9361 0 8 8.2 9054 0 7 7.17 9447 0 7 7.17 9394 0 7 7.17 9395 0 7 7.17 9422 0 7 7.17 9424 0 7 7.17 9439 0 7 7.17 9401 0 6 6.15 9412 0 6 6.15 9199 0 6 6.15 9475 0 6 6.15 8953 0 6 6.15 9443 0 6 6.15

Example 51 High Metastatic Potential Lung Cancer Versus Low Metastatic Lung Cancer Cells

The following summarizes polynucleotides that represent genes differentially expressed between high metastatic potential lung cancer cells and low metastatic potential lung cancer cells:

TABLE 75 High metastatic potential lung (lib8) > low metastatic potential lung cancer cells (lib9) SEQ ID NO: Lib 8 Clones Lib 9 Clones Lib8/Lib9 9411 35 1 48.91 9809 8 0 11.18 9190 5 0 6.99

Example 52 High Metastatic Potential Colon Cancer Versus Low Metastatic Colon Cancer Cells

Table 76 summarizes polynucleotides that represent genes differentially expressed between high metastatic potential and low metastatic potential colon cancer cells:

TABLE 76 Low metastatic potential colon (lib2) > high metastatic potential colon cancer cells (lib1) SEQ ID NO: Lib1 Clones Lib2 Clones Lib2/Lib1 8897 0 8 8.67 8943 0 6 6.5 9029 0 6 6.5

Example 53 High Tumor Potential Colon Tissue Vs. Metastasized Colon Cancer Tissue

The following table summarizes polynucleotides that represent genes differentially expressed between high tumor potential colon cancer cells and cells derived from high metastatic potential colon cancer cells of a patient.

TABLE 77 High tumor potential colon tissue (lib16) vs. high metastatic colon tissue (lib17) SEQ ID NO: Lib 16 Lib 17 Lib17/Lib16 8940 0 7 6.89 9210 3 12 3.94

Example 54 Differential Expression Across Multiple Libraries

A number of polynucleotide sequences have been identified that represent genes that are differentially expressed across multiple libraries. Expression of these sequences in a tissue or any origin can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. These polynucleotides can also serve as non-tissue specific markers of, for example, risk of metastasis of a tumor. The differential expression data for these sequences is provided in Table 78 below.

TABLE 78 Genes Differentially Expressed Across Multiple Library Comparisons SEQ ID NO: Cell or Tissue Sample and Cancer State Compared RATIO 8874 Low Met Colon (lib2) > High Met Colon (lib1) 8.67 8874 High Met Breast (lib3) > Low Met Breast (Lib4) 5.85 9049 Low Met Lung (lib9) > High Met Lung (lib8) 17.44 9049 Colon Tumor Tissue (lib16) > Normal Colon 3.42 Tissue (lib15) 9049 Colon Tumor Tissue (lib19) > Normal Colon 66.5 Tissue (lib18) 9049 High Met Colon Tissue (lib20) > Normal Colon 14.04 Tissue (lib18) 9049 Colon Tumor Tissue (lib19) > High Met Colon 4.74 Tissue (lib20) 9156 High Met Colon (lib1) > Low Met Colon (lib2) 5.76 9156 Low Met Breast (lib4) > High Met Breast (Lib3) 17.28 9485 Low Met Breast (lib4) > High Met Breast (Lib3) 6.15 9485 High Met Lung (lib8) > Low Met Lung (lib9) 19.56 9694 High Met Breast (lib3) > Low Met Breast (Lib4) 9.76 9694 HMVEC-bFGF (lib13) > HMVEC (lib12) 4.98 9694 Lung Tumor Tissue (lib24) > Normal Lung Tissue 5.94 (lib23) Key for Table 78: High Met = high metastatic potential; Low Met = low metastatic potential; met = metastasized; tumor = non-metastasized tumor; HMVEC = human microvascular endothelial cell; bFGF = bFGF treated.

Detection of expression of genes that correspond to the above polynucleotides may be of particular interest in diagnosis, prognosis, risk assesment, and monitoring of treatment. Furthermore, differential expression of a specific gene across multiple libraries can also be indicative of a gene whose expression is associated with, for example, suppression of the metastatic phenotype or with development of the cell toward a metastatic phenotype. For example, SEQ ID NO:9012 corresponds to a gene that is expressed at relatively higher levels in colon tumor tissue than in high metastatic potential colon tumor tissue, and at relatively higher levels in high metastatic potential colon tumor tissue than in normal colon tissue. Thus a relatively increased level of expression of the gene corresponding to SEQ ID NO:9012 may be used as marker of a pre-metastatic colon cells either alone or in combination with other markers.

Some polynucleotides exhibited opposite differential expression trends in libraries of different origin (see, e.g., SEQ ID NO:9119). These data suggest that the differential expression patterns of some gene associated with development of metastases indicate a unique role for those genes specific for the tissue of origin.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Deposit Information. The following materials were deposited with the American Type Culture Collection (CMCC=Chiron Master Culture Collection).

TABLE 79 Cell Lines Deposited Deposited with ATCC CMCC Cell Line Deposit Date ATCC Accession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containing specific clones, were assigned an “ES” number (internal reference) and deposited with the ATCC. Table 80 below provides the ATCC Accession Nos. of the ES deposits, all of which were deposited on or before May 13, 1999. The names of the clones contained within each of these deposits are provided in the tables 81 and 82.

TABLE 80 Pools of Clones and Libraries Deposited with ATCC on or before Sep. 23, 1999 Library No. CMCC No. ATCC Deposit No. ES55 5058 PTA-739 ES56 5059 PTA-740 ES57 5060 PTA-741 ES58 5061 PTA-742 ES59 5062 PTA-743 ES60 5063 PTA-744 ES61 5064 PTA-745 ES62 5065 PTA-746 ES63 5066 PTA-747 ES64 5067 PTA-748 ES65 5068 PTA-749 ES66 5069 PTA-750 ES67 5070 PTA-751 ES68 5071 PTA-752 ES69 5072 PTA-753 ES70 5073 PTA-754 ES71 5074 PTA-755 ES72 5075 PTA-756 ES73 5076 PTA-757 ES74 5077 PTA-758

TABLE 81 ES55 ES56 ES57 ES58 M00004170C:H06 M00004036B:C11 M00004288D:E07 M00023298B:G07 M00004170D:C06 M00004064B:G03 M00004318D:D07 M00026819B:E02 M00004171D:H10 M00004067C:E05 M00004356C:D02 M00026914C:H10 M00004174B:B12 M00004099C:F04 M00004391C:F12 M00027023B:H12 M00004175D:G10 M00004103A:E06 M00004386C:C03 M00027085A:G10 M00004176A:E07 M00004128B:H11 M00004414D:C11 M00027248D:D01 M00001352D:A09 M00004167A:H04 M00004422C:A01 M00027546B:A11 M00001345C:B10 M00004158C:B01 M00004427D:H04 M00023299B:A01 M00001382D:F03 M00004165B:E03 M00004502B:G05 M00026857A:F02 M00001419A:E01 M00004181A:B05 M00004495D:A05 M00026858C:H05 M00001437D:A12 M00003993C:G11 M00005364C:A02 M00026861A:B05 M00001441D:G02 M00004046C:A04 M00005375B:H03 M00026846C:B01 M00001601D:A03 M00004034A:G03 M00005420C:E10 M00027131A:H02 M00001677B:G01 M00004036C:E10 M00005413B:B02 M00027396A:F07 M00001678A:B10 M00004043C:A06 M00005438D:A08 M00023301B:C01 M00001675C:F05 M00004067C:C10 M00005453B:B06 M00023321B:F06 M00001360D:C12 M00004068A:A03 M00005446B:D10 M00023401C:D12 M00001389C:E01 M00004069A:E04 M00005493D:H12 M00026941C:E11 M00001390C:H05 M00004071C:B06 M00005476D:A11 M00027067A:B02 M00001399B:C04 M00004127C:C08 M00005482A:D08 M00027036B:D07 M00001507A:H06 M00004157C:E06 M00005485C:F09 M00027329A:H04 M00003747C:G12 M00004165D:H12 M00005563C:D05 M00027740C:C05 M00001358B:F12 M00003995B:C06 M00005569B:E04 M00023340A:A10 M00001360B:F09 M00004090A:B11 M00005621B:C09 M00026942C:A06 M00001392A:F02 M00004084C:F05 M00005628D:A10 M00027066A:A04 M00001397D:G04 M00004087A:H06 M00005629B:G06 M00027072C:A11 M00001463C:E12 M00004110A:G03 M00004866C:H08 M00027028A:B06 M00001531B:A03 M00004117D:F06 M00004872C:G03 M00023282B:H09 M00001507D:F09 M00004150A:B09 M00005358B:D10 M00023295B:C03 M00001513B:F05 M00004140C:D04 M00005385D:B08 M00026811A:H01 M00001514B:C02 M00004175D:D05 M00005392C:B03 M00026850B:F07 M00001576C:E03 M00004176A:H05 M00005395C:C11 M00026913D:G11 M00003756D:B09 M00004170C:A12 M00005396A:C01 M00026936D:D01 M00003907C:D02 M00004237B:G01 M00005435B:F01 M00027083C:F06 M00003926A:D01 M00004253A:E02 M00005464B:B08 M00027152D:H06 M00003928D:A04 M00003997D:G03 M00005505B:D10 M00027209D:B09 M00003935D:E04 M00003998C:D04 M00005509D:G05 M00027339D:E10 M00003985B:F06 M00004027C:E06 M00005614A:B07 M00027282D:G01 M00004063B:B12 M00004059D:A09 M00005721C:A12 M00023287A:D08 M00004101A:C12 M00004087B:D05 M00005705D:G09 M00026928A:B06 M00004104C:F06 M00004114C:B09 M00005709D:H05 M00027028B:C12 M00004107A:E02 M00004140B:C02 M00004859D:D01 M00027115B:G04 M00004108B:D04 M00004149C:D11 M00005342D:E04 M00027096B:A01 M00003856A:H10 M00004168D:F05 M00005363D:C05 M00027154B:D05 M00003908C:C04 M00004176B:H09 M00005353C:H01 M00027164A:A09 M00003895C:F05 M00004173A:D03 M00005386C:G01 M00027218C:D06 M00003939B:C02 M00004209B:G01 M00005388B:B02 M00023343B:C08 M00003997A:C08 M00004253D:D04 M00005396C:H04 M00026871C:F12 M00004066D:C02 M00004275A:H07 M00005434A:F11 M00026882A:E07 M00004105C:C05 M00004269C:B10 M00005434C:E02 M00027067B:E09 M00003788B:C08 M00004298A:H09 M00005473C:F02 M00027062C:C04 M00003788C:C05 M00004347A:F10 M00005459B:A01 M00027131C:E07 M00003835B:C05 M00004337A:A07 M00005469A:D10 M00027137D:F05 M00003820B:G04 M00004372A:A08 M00005505D:H08 M00027204B:A08 M00003888C:G08 M00004406D:E11 M00005509B:E10 M00027188A:D12 M00003977D:H04 M00004449B:B05 M00005616B:E11 M00027190B:F06 M00004029D:H03 M00004507A:F11 M00005589B:H12 M00027193A:F07 M00004034A:A05 M00004276A:C06 M00005721D:B03 M00022362D:G11 M00004140D:E03 M00004270C:H05 M00005698A:H12 M00007947B:F07 M00003775C:C01 M00004343A:G07 M00006613C:C02 M00007948B:B07 M00003776B:F08 M00004344B:C06 M00006617A:A06 M00008003B:F09 M00003839D:C03 M00004373D:G10 M00006584D:D01 M00008054C:C03 M00003818C:D02 M00004368A:G11 M00006594B:D05 M00008075D:B01 M00003820C:E08 M00004371B:A05 M00006600D:G07 M00022074A:F05 M00003822A:D02 M00004403A:A02 M00006631D:G09 M00007943C:B02 M00003877C:G01 M00004445D:A04 M00006635A:C01 M00008002B:F09 M00003880A:G10 M00004447A:A10 M00006726D:H10 M00021653C:B06 M00003919D:F01 M00004603D:D09 M00006874D:E01 M00021851D:H06 M00003960D:E09 M00004326D:D06 M00006882C:D03 M00022015D:C11 M00004081A:E11 M00004323B:G12 M00006925B:B02 M00022018B:E09 M00004085B:D12 M00004350A:C04 M00006946B:C08 M00022095C:F03 M00004142C:A06 M00004357A:B10 M00006949B:C07 M00007996C:B11 M00004135D:D01 M00004360B:B08 M00007026A:A03 M00007977B:C11 M00004198B:G08 M00004385D:D06 M00006712A:F01 M00008088D:B01 M00004185B:H03 M00004414D:A01 M00006727A:H12 M00021676B:B12 M00004187A:B05 M00004415A:A01 M00006815D:D11 M00021972A:C10 M00004251B:H12 M00004423A:B05 M00006805D:H12 M00022099C:A10 M00004232D:G11 M00004423C:F03 M00006934B:B11 M00022106D:B06 M00004240A:D03 M00004426B:H06 M00007019B:G01 M00007978B:C04 M00004285C:B06 M00004504C:G07 M00007038D:D01 M00008053D:E09 M00004292A:C08 M00004466A:E04 M00007041C:C05 M00021669B:G02 M00004335A:G05 M00004498D:A11 M00006630A:E05 M00022118A:D08 M00004240C:A06 M00004292A:F03 M00006623C:G07 M00022251A:F07 M00004249A:C09 M00004280D:D10 M00006694D:G06 M00022235D:F07 M00004335D:D03 M00004286D:D02 M00006668D:B10 M00022240C:B03 M00004378A:H10 M00004870D:E05 M00006688A:F09 M00022406C:G03 M00004381A:E10 M00004871C:C04 M00006745B:C05 M00022459C:G05 M00004444C:H11 M00004872A:D07 M00006846A:B03 M00022627B:D01 M00004225A:E03 M00005395D:D11 M00006823A:H06 M00022184D:F07 M00004284A:C09 M00005395D:B12 M00006925A:B09 M00022177D:G02 M00004264B:F03 M00005412D:G07 M00006894D:A07 M00022460C:E12 M00004404C:B03 M00005413D:G12 M00006895D:A02 M00022627A:A02 M00004410A:F06 M00005513A:H01 M00006991B:E05 M00022144D:D09 M00004412A:G05 M00005515D:G02 M00006994A:C12 M00022203B:A05 M00001340C:A08 M00005607A:C08 M00007046D:E10 M00022214C:C11 M00001340C:D09 M00005366D:E12 M00006577A:B01 M00022252C:A04 M00001395D:B04 M00005618C:H11 M00006630A:E09 M00022420B:C08 M00001466C:H11 M00005708C:D11 M00006619A:G11 M00022640B:G10 M00001528D:B12 M00005810B:C07 M00006704A:C11 M00022641C:H03 M00001517C:A10 M00006795C:B12 M00022127C:E01 M00022652B:G06 M00001561A:G10 M00006755C:C03 M00022128A:C05 M00022216C:H02 M00001565C:F06 M00006756D:G07 M00022176D:F05 M00022199A:F09 M00001569A:H01 M00006779D:F03 M00022214A:H05 M00022214A:D01 M00001341A:H10 M00004821D:C03 M00022220B:B06 M00022273A:B03 M00001375C:C11 M00005358A:H03 M00022278C:E04 M00022256D:G11 M00001397C:F01 M00005480C:A04 M00022282A:A11 M00022261C:D06 M00001431A:F03 M00005481C:H05 M00022260C:H07 M00022490B:G12 M00001457D:E08 M00005490B:B02 M00022263A:C01 M00022648D:G11 M00001505C:C10 M00005820A:H11 M00022377A:E02 M00022709A:G02 M00001615A:D01 M00006621B:B06 M00022399C:B02 M00022701C:A05 M00001618C:E01 M00006752C:D04 M00022056C:D12 M00022826A:C08 M00001358C:D09 M00006757D:H04 M00022087A:D01 M00022963A:E07 M00001360B:B01 M00005000A:H05 M00022088B:E05 M00022904D:D04 M00001391C:B05 M00005296D:G03 M00022090D:B03 M00023095C:A09 M00001389B:B12 M00005378B:B04 M00022094A:A09 M00022684C:C12 M00001485A:C04 M00005461C:D11 M00022096B:D10 M00022765B:E03 M00001559D:E02 M00005464D:D07 M00022176A:F02 M00022898C:H07 M00001545D:F12 M00005657B:F11 M00022217B:E03 M00022902B:F10 M00001549C:F10 M00006596D:H02 M00022259A:D04 M00023003A:H01 M00001579C:E07 M00005826B:F10 M00022381B:C12 M00022768A:A10 M00001630A:E08 M00006577B:F01 M00022399D:A07 M00022834A:H02 M00001386B:E01 M00006582A:F12 M00022401C:G07 M00023002A:C02 M00001389A:F03 M00006664A:C05 M00022407D:G07 M00023003C:C10 M00001418C:F06 M00006678C:B07 M00022417B:C01 M00023012A:C06 M00001454D:H09 M00006840A:A12 M00022435C:C05 M00007973D:B03 M00001442D:D09 M00005020B:D10 M00022471D:A05 M00007939A:F06 M00001450D:H12 M00005296B:H07 M00022464D:F12 M00007941D:D07 M00001479D:B10 M00005403A:D12 M00022469A:A05 M00007948D:F08 M00001598C:F02 M00005376B:E08 M00022500B:D01 M00008012D:H04 M00001594A:H01 M00005378C:B12 M00022506D:B03 M00008014D:A11 M00001657D:D07 M00005397A:G08 M00022542A:B06 M00008048C:A08 M00003772C:F12 M00005449D:D04 M00022527D:A09 M00008099A:C12 M00003844D:B02 M00005465A:A07 M00022568B:D03 M00021668D:G09 M00003845B:A04 M00005648C:C11 M00022561D:E06 M00021861C:B08 M00003845C:F08 M00006595C:B08 M00022687C:C11 M00021980A:F03 M00003848A:E08 M00006816D:D08 M00022695D:B02 M00007931A:B07 M00003880C:D06 M00006835D:C08 M00022425A:F11 M00007948C:G01 M00001647D:A02 M00006914C:D07 M00022434D:B06 M00007969B:E10 M00001655C:F07 M00007177A:G07 M00022460D:C07 M00008012B:C05 M00003804D:F12 M00006920B:H07 M00022510A:B09 M00008012D:E07 M00003884C:G09 M00007161C:D12 M00022501D:A09 M00008014C:H01 M00003916D:A10 M00006968D:H02 M00022541D:G06 M00008016C:E06 M00003943B:C12 M00006936C:G11 M00022527B:H05 M00008052C:G11 M00003935A:C04 M00006945D:A07 M00022538D:B02 M00008054C:E07 M00003937D:F09 M00007047C:H04 M00022559D:F10 M00008093C:G08 M00001683B:F12 M00007065D:A03 M00022569D:H03 M00021614A:C09 M00001669B:H04 M00007079D:H01 M00022601A:A09 M00008094D:C02 M00003762D:C02 M00006968A:H05 M00022604A:F06 M00021667C:G10 M00003788D:E06 M00007078B:H04 M00022684B:F11 M00021674A:B07 M00003824A:B11 M00007186A:A12 M00022702A:D10 M00021846B:F05 M00003865B:D10 M00004852B:H08 M00022691A:G01 M00021847B:A09 M00003870C:H03 M00005382A:G09 M00022696A:H03 M00021963C:H04 M00003901B:C02 M00005418C:B09 M00022444B:C04 M00007985C:G07 M00003893A:D03 M00005420C:E03 M00022447A:H06 M00008001D:F11 M00003931A:G01 M00005450C:G09 M00022488C:H02 M00007992A:G04 M00003973A:D09 M00005444D:D01 M00022522B:A05 M00008000D:B06 M00001660A:B10 M00005494C:F08 M00022513C:G04 M00008001A:G11 M00003761C:C05 M00005479C:A05 M00022517C:B01 M00008044C:A05 M00003829C:G07 M00005486A:F07 M00022546B:F12 M00008085B:G01 M00003833D:F11 M00005538C:H11 M00022591C:F03 M00008082B:C05 M00003879D:A09 M00005648C:E10 M00022617B:A01 M00008083A:H11 M00003880B:B08 M00005621A:B05 M00022681D:H10 M00021624B:E11 M00003861D:G10 M00004847D:G01 M00022659B:C01 M00021689A:G05 M00003876C:G11 M00005342B:G01 M00022664C:G10 M00021865B:F06 M00003877C:C11 M00005305A:H01 M00022711B:A05 M00021879B:C11 M00003902C:D02 M00026906B:G03 M00022704A:H08 M00021958A:A03 M00003933A:B04 M00026872A:C10 M00022449D:B05 M00021945A:B04 M00003923D:A03 M00026964C:H02 M00022548A:F02 M00021981D:A11 M00003989D:A02 M00026982C:D08 M00022590D:E08 M00007987A:D10 M00003991A:D05 M00027069D:F02 M00022622A:E08 M00007998C:B04 M00004030C:E05 M00027042D:E02 M00022655A:F09 M00008001B:E11 M00004048A:E10 M00027056B:H07 M00022664A:E04 M00008045A:B05 M00006680D:A01 M00027137C:A03 M00022720A:C01 M00008023A:B03 M00006688C:C12 M00027184D:H02 M00022722D:C07 M00008027D:H09 M00006740A:A06 M00027189C:D04 M00022746D:D05 M00008044B:F07 M00006757A:C09 M00027196A:A10 M00022772A:A06 M00008089C:B08 M00006859D:E11 M00027357D:A02 M00022813C:B09 M00021620D:B06 M00006917B:C05 M00027369A:B03 M00022853D:C05 M00021624B:D03 M00006919A:H12 M00027439B:A09 M00022843A:D02 M00021628C:B09 M00006993B:F02 M00027393D:F01 M00022844C:A01 M00021680D:H08 M00007093C:C11 M00027557D:B06 M00022968D:G06 M00021687C:A04 M00007047D:C02 M00027502C:H02 M00023023B:A05 M00021696C:E02 M00007064B:E09 M00027507C:C06 M00022716A:C01 M00021698A:H03 M00007121A:G04 M00027529B:B11 M00022725D:G05 M00021864C:C07 M00007107C:D02 M00027438D:A03 M00022817D:B09 M00021958A:A04 M00007178D:A10 M00027388A:G05 M00022848D:H09 M00021949D:A05 M00007156D:E11 M00027396C:B06 M00022884D:A07 M00021951B:A01 M00007172D:H03 M00027551C:B07 M00022983A:H04 M00022001B:H10 M00007175D:G02 M00027518B:B07 M00023034B:B10 M00022001D:E06 M00007121D:A11 M00027528A:G03 M00023038D:D04 M00022071D:C08 M00007101C:H01 M00027759B:E11 M00022743C:G05 M00022078B:B04 M00007104D:D10 M00027728A:B03 M00022734C:A03 M00022113B:A12 M00007116A:C08 M00027484A:G03 M00022737D:B02 M00022138C:B07 M00007152A:A10 M00027752B:E05 M00022801A:G04 M00022152A:G05 M00007179B:H04 M00022838B:E05 M00022158C:C08 M00007157B:B04 M00022856A:B09 M00022192B:H07 M00007167C:B10 M00022902C:F11 M00022233C:D11 M00007175B:B11 M00022893D:C06 M00022252A:C01 M00007177B:C02 M00022922D:G06 M00022370A:G07 M00007141A:G08 M00022986B:C02 M00022300A:A05 M00007196D:D02 M00023002D:C12 M00022386D:C04 M00007145C:B05 M00023096C:A03 M00022072D:E12 M00007126D:H01 M00023097A:C03 M00022102D:A10 M00007140C:G12 M00022743C:G06 M00022207C:C01 M00007200A:B12 M00022736B:B03 M00022249C:G09 M00007203C:E06 M00022737B:F12 M00022383C:F05 M00022831C:F11 M00022384B:E06 M00022836C:A07 M00022067A:B03 M00022854D:C04 M00022056B:G12 M00022860A:A07 M00022084B:C03 M00022861C:B04 M00022087D:F12 M00023096A:F03 M00023096D:B11 M00023097C:D10

TABLE 82 ES59 ES60 ES61 ES62 M00001418A:A02 M00001477A:G02 M00004450A:G07 M00005515B:B08 M00003877C:A08 M00003853C:A09 M00004353D:C06 M00005385B:A10 M00003977C:D01 M00001694B:H12 M00004406A:H12 M00005516D:F12 M00004295A:C02 M00001664D:E02 M00004048C:C02 M00005822D:C05 M00001383C:C04 M00003847B:H01 M00004170B:G04 M00004841C:H03 M00001500A:A02 M00001631D:G08 M00004108C:D07 M00005810B:G02 M00003880B:D03 M00004498D:F02 M00004125B:A02 M00007107A:H08 M00003803B:G12 M00001563A:F04 M00004109A:B07 M00004825A:G12 M00003819D:B02 M00001558D:E02 M00004123B:G05 M00005327C:G08 M00004178B:F07 M00004278C:H11 M00004152A:F03 M00005390C:E05 ES63 ES64 ES65 ES66 M00005520A:H11 M00006790D:F10 M00027175D:A05 M00026949A:F04 M00006814D:D09 M00006627C:C02 M00026910C:C05 M00023432D:F09 M00006918D:G08 M00027462D:A12 M00027280D:H01 M00027178B:E04 M00007197D:D12 M00026972A:F04 M00023289D:E06 M00027225B:D03 M00005497C:G08 M00027592D:C05 M00023373A:D01 M00023340B:B07 M00007109D:G01 M00026945B:C10 M00027231A:D01 M00027283C:H12 M00005377C:F07 M00027231C:D08 M00023321A:F07 M00027085C:H12 M00006813B:E04 M00027083D:F06 M00027266C:G12 M00027234C:B05 M00005825A:A10 M00027142A:C01 M00023398D:F10 M00023390A:C04 M00005416B:A01 M00027607A:A09 M00027603C:E02 M00026810A:H04 ES67 ES68 ES69 ES70 M00023340B:H12 M00027642C:D11 M00022714B:D04 M00022709A:C01 M00027237C:D04 M00027202B:B09 M00022838A:H05 M00022413B:D07 M00026809C:D10 M00027459A:G12 M00022392C:H06 M00022467C:H07 M00027386D:C02 M00027250A:C04 M00022363C:D03 M00022561B:B09 M00027343B:H05 M00027499B:G02 M00022205A:C02 M00022214C:E09 M00027356A:H02 M00027053C:B06 M00022717C:F05 M00022697A:C08 M00027363D:A08 M00027598C:D06 M00008015B:D08 M00022682A:F10 M00027364D:E08 M00006989C:B01 M00021625B:G07 M00021841A:E11 M00027618A:B08 M00006837B:H12 M00008100D:C08 M00021691B:E04 M00027628D:D08 M00007202A:A09 M00022669D:G07 M00022477C:C07 ES71 ES72 ES73 ES74 M00022134D:D12 M00008028D:B01 M00022513C:E10 M00023363C:A04 M00022705B:F08 M00021931B:F04 M00022518C:C04 M00001401B:A02 M00022903D:H02 M00008097C:E04 M00022544C:D08 M00008023C:A06 M00022915C:C09 M00008082B:H10 M00022785C:B10 M00022077D:A12 M00007965C:B02 M00008006A:H02 M00022525C:E09 M00023284B:G06 M00022368C:C11 M00022167B:H02 M00022641D:F08 M00023369D:C05 M00007937C:E08 M00022509D:A12 M00022923A:A09 M00023413D:F04 M00021852C:D12 M00022169A:E11 M00026905A:G11 M00008000D:G11 M00022184D:H07 M00027169D:H06 M00021908B:F03 M00022441B:A06 M00005434D:H02

The deposits described herein are provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where the ATCC deposit is composed of a pool of cDNA clones or a library of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones in the pool or library were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

Example 55 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

Cell lines and human normal and tumor tissue were used to construct cDNA libraries from mRNA isolated from the cells and tissues. Most sequences were about 275-300 nucleotides in length. The cells lines include Km12L4-A cell line, a high metastatic colon cancer cell line (Morika, W. A. K. et al., Cancer Research (1988) 48:6863). The KM12L4-A cell line is derived from the KM12C cell line. The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B2 surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM 12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as model cell lines for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al., Clin. Exp. Metastasis (1996) 14:246). These and other cell lines and tissue are described in Table 88.

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale. Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. The sequences remaining after masking were then used in a BLASTN vs. Genbank search; sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the Genbank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded. Second, a BLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p valueless than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 3351 sequences listed in the accompanying Sequence Listing. Each identified polynucleotide represents sequence from at least a partial mRNA transcript. Polynucleotides that were determined to be novel were assigned a sequence identification number.

The novel polynucleotides were assigned sequence identification numbers SEQ ID NOs:9920-12191. The DNA sequences corresponding to the novel polynucleotides are provided in the Sequence Listing. Tables 83 and 84 and 2 provide: 1) the SEQ ID NO assigned to each sequence for use in the present specification or a corresponding number; 2) the sequence name used as an internal identifier of the sequence; 3) the name assigned to the clone from which the sequence was isolated; and 4) the number of the cluster to which the sequence is assigned (Cluster ID; where the cluster ID is 0, the sequence was not assigned to any cluster).

Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOs: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene.

Example 56 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOs:9920-13270 were translated in all three reading frames to determine the best alignment with the individual sequences. These amino acid sequences and nucleotide sequences are referred to, generally, as query sequences, which are aligned with the individual sequences. Query and individual sequences were aligned using the BLAST programs, available over the world wide web at the web site ncbi.nlm.nih.gov/BLAST/. Again the sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above.

Tables 85 and 86 (inserted before the claims) show the results of the alignments. Tables 85 and 86 refer to each sequence by its SEQ ID NO or a corresponding number, the accession numbers and descriptions of nearest neighbors from the Genbank and Non-Redundant Protein searches, and the p values of the search results.

The activity of the polypeptide encoded by SEQ ID NOs:9920-13270 is the same or similar to the nearest neighbor reported in Table 85 or 86. The accession number of the nearest neighbor is reported, providing a reference to the activities exhibited by the nearest neighbor. The search program and database used for the alignment also are indicated as well as a calculation of the p value.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of SEQ ID NOs: 9920-13270. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of SEQ ID NOs: 9920-132701.

Example 57 Members of Protein Families

The sequences were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 87). “Start” and “stop” in Table 3 indicate the position within the individual sequences that align with the query sequence having the indicated SEQ ID NO. The direction indicates the orientation of the query sequence with respect to the individual sequence, where forward (for) indicates that the alignment is in the same direction (left to right) as the sequence provided in the Sequence Listing and reverse (rev) indicates that the alignment is with a sequence complementary to the sequence provided in the Sequence Listing.

Some polynucleotides exhibited multiple profile hits because, for example, the particular sequence contains overlapping profile regions, and/or the sequence contains two different functional domains. These profile hits are described in more detail below.

Ank Repeats (ANK). Some SEQ ID NOs represent polynucleotides encoding an Ank repeat-containing protein. The ankyrin motif is a 33 amino acid sequence named for the protein ankyrin which has 24 tandem 33-amino-acid motifs. Ank repeats were originally identified in the cell-cycle-control protein cdc10 (Breeden et al., Nature (1987) 329:651). Proteins containing ankyrin repeats include ankyrin, myotropin, I-kappaB proteins, cell cycle protein cdc10, the Notch receptor (Matsuno et al., Development (1997) 124(21):4265); G9a (or BAT8) of the class III region of the major histocompatibility complex (Biochem J. 290:811-818, 1993), FABP, GABP, 53BP2, Lin12, glp-1, SW14, and SW16. The functions of the ankyrin repeats are compatible with a role in protein-protein interactions (Bork, Proteins (1993) 17(4):363; Lambert and Bennet, Eur. J. Biochem. (1993) 211:1; Kerr et al., Current Op. Cell Biol. (1992) 4:496; Bennet et al., J. Biol. Chem. (1980) 255:6424).

ATPases Associated with Various Cellular Activities (ATPases). Some SEQ ID NOs correspond to a sequence that encodes a novel member of the “ATPases Associated with diverse cellular Activities” (AAA) protein family. The AAA protein family is composed of a large number of ATPases that share a conserved region of about 220 amino acids that contains an ATP-binding site (Froehlich et al., J. Cell Biol. (1991) 114:443; Erdmann et al., Cell (1991) 64:499; Peters et al., EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieri et al., BioEssays (1995) 17:639; see internet website at yeamob.pci.chemie.uni-tuebingen.de/AAA/Description.-html). The proteins that belong to this family either contain one or two AAA domains. In general, the AAA domains in these proteins act as ATP-dependent protein clamps (Confalonieri et al. (1995) BioEssays 17:639). In addition to the ATP-binding ‘A’ and ‘B’ motifs, which are located in the N-terminal half of this domain, there is a highly conserved region located in the central part of the domain which was used in the development of the signature pattern.

Bromodomain (bromodomain). One SEQ ID NO represents a polynucleotide encoding a polypeptide having a bromodomain region (Haynes et al., 1992, Nucleic Acids Res. 20:2693-2603, Tamkun et al., 1992, Cell 68:561-572, and Tamkun, 1995, Curr. Opin. Genet. Dev. 5:473-477), which is a conserved region of about 70 amino acids. The bromodomain is thought to be involved in protein-protein interactions and may be important for the assembly or activity of multicomponent complexes involved in transcriptional activation.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP). Some SEQ ID NOs represent polynucleotides encoding a novel member of the family of basic region plus leucine zipper transcription factors. The bZIP superfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcription factors encompasses proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper required for dimerization.

EF Hand (EFhand). Some SEQ ID NOs correspond to polynucleotides encoding a novel protein in the family of EF-hand proteins. Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand (Kawasaki et al., Protein. Prof. (1995) 2:305-490). This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).

Ets Domain (Ets_Nterm). One SEQ ID NO represents a polynucleotide encoding a polypeptide with N-terminal homology in ETS domain. Proteins of this family contain a conserved domain, the “ETS-domain,” that is involved in DNA binding. The domain appears to recognize purine-rich sequences; it is about 85 to 90 amino acids in length, and is rich in aromatic and positively charged residues (Wasylyk, et al., Eur. J. Biochem. (1993) 211:718). The ets gene family encodes a novel class of DNA-binding proteins, each of which binds a specific DNA sequence and comprises an ets domain that specifically interacts with sequences containing the common core tri-nucleotide sequence GGA. In addition to an ets domain, native ets proteins comprise other sequences which can modulate the biological specificity of the protein. Ets genes and proteins are involved in a variety of essential biological processes including cell growth, differentiation and development, and three members are implicated in oncogenic process.

G-Protein Alpha Subunit (G-alpha). One SEQ ID NO represents a polynucleotide encoding a novel polypeptide of the G-protein alpha subunit family. Guanine nucleotide binding proteins (G-proteins) are a family of membrane-associated proteins that couple extracellularly-activated integral-membrane receptors to intracellular effectors, such as ion channels and enzymes that vary the concentration of second messenger molecules. G-proteins are composed of 3 subunits (alpha, beta and gamma) which, in the resting state, associate as a trimer at the inner face of the plasma membrane. The alpha subunit binds GTP and exhibits GTPase activity. G-protein alpha subunits are 350-400 amino acids in length and have molecular weights in the range 40-45 kDa. Seventeen distinct types of alpha subunit have been identified in mammals, and fall into 4 main groups on the basis of both sequence similarity and function: alpha-s, alpha-q, alpha-i and alpha-12 (Simon et al., Science (1993) 252:802). They are often N-terminally acylated, usually with myristate and/or palmitoylate, and these fatty acid modifications can be important for membrane association and high-affinity interactions with other proteins.

Helicases conserved C-terminal domain (helicase_C). Some SEQ ID NOs represent polynucleotides encoding novel members of the DEAD/H helicase family. A number of eukaryotic and prokaryotic proteins have been characterized (Schmid S. R., et al., Mol. Microbiol. (1992) 6:283; Linder P., et al., Nature (1989) 337:121; Wassarman D. A., et al., Nature (1991) 349:463) on the basis of their structural similarity. All are involved in ATP-dependent, nucleic-acid unwinding. All DEAD box family members of the above proteins share a number of conserved sequence motifs, some of which are specific to the DEAD family while others are shared by other ATP-binding proteins or by proteins belonging to the helicases ‘superfamily’ (Hodgman T. C., Nature (1988) 333:22 and Nature (1988) 333:578 (Errata). One of these motifs, called the “D-E-A-D-box”, represents a special version of the B motif of ATP-binding proteins. Some other proteins belong to a subfamily which have His instead of the second Asp and are thus said to be “D-E-A-H-box” proteins (Wassarman D. A., et al., Nature (1991) 349:463; Harosh I., et al., Nucleic Acids Res. (1991) 19:6331; Koonin E. V. et al., J. Gen. Virol. (1992) 73:989.

Homeobox domain (homeobox). Some SEQ ID NOs represent polynucleotides encoding proteins having a homeobox domain. The homeobox is a protein domain of 60 amino acids (Gehring In: Guidebook to the Homeobox Genes, Duboule D., Ed., pp. 1-10, Oxford University Press, Oxford, (1994); Buerglin In: Guidebook to the Homeobox Genes, pp 25-72, Oxford University Press, Oxford, (1994); Gehring, Trends Biochem. Sci. (1992) 17:277-280; Gehring et al., Annu. Rev. Genet. (1986) 20:147-173; Schofield, Trends Neurosci. (1987) 10:3-6) first identified in a number of Drosophila homeotic and segmentation proteins. It is extremely well conserved in many other animals, including vertebrates. This domain binds DNA through a helix-turn-helix type of structure. Several proteins that contain a homeobox domain play an important role in development. Most of these proteins are sequence-specific DNA-binding transcription factors. The homeobox domain is also very similar to a region of the yeast mating type proteins. These are sequence-specific DNA-binding proteins that act as master switches in yeast differentiation by controlling gene expression in a cell type-specific fashion.

A schematic representation of the homeobox domain is shown below. The helix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’ (for turn).

The pattern detects homeobox sequences 24 residues long and spans positions 34 to 57 of the homeobox domain.

MAP kinase kinase (mkk). Some SEQ ID NOs represent novel members of the MAP kinase kinase family. MAP kinases (MAPK) are involved in signal transduction, and are important in cell cycle and cell growth controls. The MAP kinase kinases (MAPKK) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKKs are essential transducers through which signals must pass before reaching the nucleus. For review, see, e.g., Biologique Biol Cell (1993) 79:193-207; Nishida et al., Trends Biochem Sci (1993) 18:128-31; Ruderman, Curr Opin Cell Biol (1993) 5:207-13; Dhanasekaran et al., Oncogene (1998) 17:1447-55; Kiefer et al., Biochem Soc Trans (1997) 25:491-8; and Hill, Cell Signal (1996) 8:533-44.

Protein Kinase (protkinase). Some SEQ ID NOs represent polynucleotides encoding protein kinases. Protein kinases catalyze phosphorylation of proteins in a variety of pathways, and are implicated in cancer. Eukaryotic protein kinases (Hanks S. K., et al., FASEB J. (1995) 9:576; Hunter T., Meth. Enzymol. (1991) 200:3; Hanks S. K., et al., Meth. Enzymol. (1991) 200:38; Hanks S. K., Curr. Opin. Struct. Biol. (1991) 1:369; Hanks S. K. et al., Science (1988) 241:42) are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. The first region, which is located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. The second region, which is located in the central part of the catalytic domain, contains a conserved aspartic acid residue which is important for the catalytic activity of the enzyme (Knighton D. R. et al., Science (1991) 253:407). The protein kinase profile includes two signature patterns for this second region: one specific for serine/threonine kinases and the other for tyrosine kinases. A third profile is based on the alignment in (Hanks S. K. et al., FASEB J. (1995) 9:576) and covers the entire catalytic domain.

If a protein analyzed includes two of the above protein kinase signatures, the probability of it being a protein kinase is close to 100%.

Ras family proteins (ras). Some SEQ ID NOs represent polynucleotides encoding novel members of the ras family of small GTP/GDP-binding proteins (Valencia et al., 1991, Biochemistry 30:4637-4648). Ras family members generally require a specific guanine nucleotide exchange factor (GEF) and a specific GTPase activating protein (GAP) as stimulators of overall GTPase activity. Among ras-related proteins, the highest degree of sequence conservation is found in four regions that are directly involved in guanine nucleotide binding. The first two constitute most of the phosphate and Mg2+ binding site (PM site) and are located in the first half of the G-domain. The other two regions are involved in guanosine binding and are located in the C-terminal half of the molecule. Motifs and conserved structural features of the ras-related proteins are described in Valencia et al., 1991, Biochemistry 30:4637-4648.

Thioredoxin family active site (Thioredox). One SEQ ID NO represents a polynucleotide encoding a protein having a thioredoxin family active site. Thioredoxins (Holmgren A., Annu. Rev. Biochem. (1985) 54:237; Gleason F. K. et al., FEMS Microbiol. Rev. (1988) 54:271; Holmgren, A. J. Biol. Chem. (1989) 264:13963; Eklund H. et al., Proteins (1991) 11:13) are small proteins of approximately one hundred amino-acid residues which participate in various redox reactions via the reversible oxidation of an active center disulfide bond. They exist in either a reduced form or an oxidized form where the two cysteine residues are linked in an intramolecular disulfide bond. Thioredoxin is present in prokaryotes and eukaryotes and the sequence around the redox-active disulfide bond is well conserved.

Trypsin (trypsin). One SEQ ID NO corresponds to a novel serine protease of the trypsin family. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved in this family of proteases (Brenner S., Nature (1988) 334:528).

WD Domain G-Beta Repeats (WD_domain). Some SEQ ID NOs represent novel members of the WD domain/G-beta repeat family. Beta-transducin (G-beta) is one of the three subunits (alpha, beta, and gamma) of the guanine nucleotide-binding proteins (G proteins) which act as intermediaries in the transduction of signals generated by transmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds to and hydrolyzes GTP; the functions of the beta and gamma subunits are less clear but they seem to be required for the replacement of GDP by GTP as well as for membrane anchoring and receptor recognition. In higher eukaryotes, G-beta exists as a small multigene family of highly conserved proteins of about 340 amino acid residues. Structurally, G-beta consists of eight tandem repeats of about 40 residues, each containing a central Trp-Asp motif (this type of repeat is sometimes called a WD-40 repeat).

wnt Family of Developmental Signaling Proteins (Wnt_dev_sign). One SEQ ID NO corresponds to a novel member of the wnt family of developmental signaling proteins. Wnt-1 (previously known as int-1), the seminal member of this family, (Nusse R., Trends Genet. (1988) 4:291) is thought to play a role in intercellular communication and seems to be a signalling molecule important in the development of the central nervous system (CNS). All wnt family proteins share the following features characteristics of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines that are probably involved in disulfide bonds. The Wnt proteins seem to adhere to the plasma membrane of the secreting cells and are therefore likely to signal over only few cell diameters.

Protein Tyrosine Phosphatase (Y_phosphatase). One SEQ ID NO represents a polynucleotide encoding a protein tyrosine kinase. Tyrosine specific protein phosphatases (EC 3.1.3.48) (PTPase) (Fischer et al., Science (1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463; Trowbridge, J. Biol. Chem. (1991) 266:23517; Tonks et al., Trends Biochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013) catalyze the removal of a phosphate group attached to a tyrosine residue. These enzymes are very important in the control of cell growth, proliferation, differentiation and transformation. Multiple forms of PTPase have been characterized and can be classified into two categories: soluble PTPases and transmembrane receptor proteins that contain PTPase domain(s). Structurally, all known receptor PTPases are made up of a variable length extracellular domain, followed by a transmembrane region and a C-terminal catalytic cytoplasmic domain. PTPase domains consist of about 300 amino acids. The search of two conserved cysteines has been shown to be absolutely required for activity. Furthermore, a number of conserved residues in its immediate vicinity have also been shown to be important.

Zinc Finger C2H2 Type (Zincfing_C2H2). Some SEQ ID NOs correspond to polynucleotides encoding novel members of the of the C2H2 type zinc finger protein family. Zinc finger domains (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99) are nucleic acid-binding protein structures. In addition to the conserved zinc ligand residues, it has been shown that a number of other positions are also important for the structural integrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved position is found four residues after the second cysteine; it is generally an aromatic or aliphatic residue.

Src homology 2. Some SEQ ID NOs represent polynucleotides encoding novel members of the family of Src homology 2 (SH2) proteins. The Src homology 2 (SH2) domain is a protein domain of about 100 amino acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps (Sadowski I. et al., Mol. Cell. Biol. 6:4396-4408 (1986)). Similar sequences are found in many other intracellular signal-transducing proteins (Russel R. B. et al., FEBS Lett. 304:15-20 (1992)). SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific and phosphorylation-dependent manner (Marangere L. E. M., Pawson T., J. Cell Sci. Suppl. 18:97-104 (1994); Pawson T., Schlessinger J., Curr. Biol. 3:434-442 (1993); Mayer B. J., Baltimore D., Trends Cell. Biol. 3:8-13 (1993); Pawson T., Nature 373:573-580 (1995)).

The SH2 domain has a conserved 3D structure consisting of two alpha helices and six to seven beta-strands. The core of the domain is formed by a continuous beta-meander composed of two connected beta-sheets (Kuriyan J., Cowburn D., Curr. Opin. Struct. Biol. 3:828-837(1993)). The profile to detect SH2 domains is based on a structural alignment consisting of 8 gap-free blocks and 7 linker regions totaling 92 match positions.

Src homology 3. Some SEQ ID NOs represent polynucleotides encoding novel members of the family of Src homology 3 (SH3) proteins. The Src homology 3 (SH3) domain is a small protein domain of about 60 amino acid residues first identified as a conserved sequence in the non-catalytic part of several cytoplasmic protein tyrosine kinases (e.g., Src, Abl, Lck) (Mayer B. J. et al., Nature 332:272-275 (1988)). Since then, it has been found in a great variety of other intracellular or membrane-associated proteins (Musacchio A. et al., FEBS Lett. 307:55-61 (1992); Pawson T., Schlessinger J., Curr. Biol. 3:434-442 (1993); Mayer B. J., Baltimore D., Trends Cell Biol. 3:8-13 (1993); Pawson T., Nature 373:573-580 (1995)).

The SH3 domain has a characteristic fold which consists of five or six beta strands arranged as two tightly packed anti-parallel beta sheets. The linker regions may contain short helices (Kuriyan J., Cowburn D., Curr. Opin. Struct. Biol. 3:828-837 (1993)).

The function of the SH3 domain may be to mediate assembly of specific protein complexes via binding to proline-rich peptides (Morton C. J., Campbell I. D., Curr. Biol. 4:615-617 (1994)).

In general SH3 domains are found as single copies in a given protein, but there are a significant number of proteins with two SH3 domains and a few with 3 or 4 copies.

Fibronectin type III. Some SEQ ID NOs represent polynucleotides encoding novel members of the family of fibronectin type III proteins. A number of receptors for lymphokines, hematopoeitic growth factors and growth hormone-related molecules have been found to share a common binding domain. (Bazan J. F., Biochem. Biophys. Res. Commun. 164:788-795 (1989); Bazan J. F., Proc. Natl. Acad. Sci. U.S.A. 87:6934-6938 (1990); Cosman D. et al., Trends Biochem. Sci. 15:265-270 (1990); d'Andrea A. D., Fasman G. D., Lodish H. F., Cell 58:1023-1024 (1989); d'Andrea A. D., Fasman G. D., Lodish H. F., Curr. Opin. Cell Biol. 2:648-651 (1990)).

The conserved region constitutes all or part of the extracellular ligand-binding region and is about 200 amino acid residues long. In the N-terminal of this domain there are two pairs of cysteines known, in the growth hormone receptor, to be involved in disulfide bonds.

Two patterns detect this family of receptors. The first one is derived from the first N-terminal disulfide loop, the second is a tryptophan-rich pattern located at the C-terminal extremity of the extracellular region.

LIM domain containing proteins. Some SEQ ID NOs represent polynucleotides encoding novel members of the family of LIM domain containing proteins. A number of proteins contain a conserved cysteine-rich domain of about 60 amino-acid residues. (Freyd G. et al., Nature 344:876-879 (1990); Baltz R. et al., Plant Cell 4:1465-1466 (1992); Sanchez-Garcia I., Rabbitts T. H., Trends Genet. 10:315-320 (1994)).

In the LIM domain, there are seven conserved cysteine residues and a histidine.

C2 domain (protein kinase C like). Some SEQ ID NOs represent polynucleotides encoding novel members of the family of C2 domain containing proteins. Some isozymes of protein kinase C (PKC) contain a domain, known as C2, of about 116 amino-acid residues, which is located between the two copies of the C1 domain (that bind phorbol esters and diacylglycerol) and the protein kinase catalytic domain. (Azzi A. et al., Eur. J. Biochem. 208:547-557 (1992); Stabel S., Semin. Cancer Biol. 5:277-284 (1994)).

The C2 domain is involved in calcium-dependent phospholipid binding (Davletov B. A., Suedhof T. C., J. Biol. Chem. 268:26386-26390 (1993)). Since domains related to the C2 domain are also found in proteins that do not bind calcium, other putative functions for the C2 domain include binding to inositol-1,3,5-tetraphosphate. (Fukuda M., et al., J. Biol. Chem. 269:29206-29211 (1994).)

The consensus pattern for the C2 domain is located in a conserved part of that domain, the connecting loop between beta strands 2 and 3. The profile for the C2 domain covers the total domain.

Serine proteases, trypsin family, active sites. One SEQ ID NO represents a polynucleotide encoding a novel member of the family of serine protease, trypsin proteins. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved in this family of proteases (Brenner S., Nature 334:528-530 (1988)).

RNA Recognition Motif Domain (RRM, RBD, or RNP). Some SEQ ID NOs represent polynucleotides encoding novel members of the family of RNA recognition motif domain proteins (Bandziulis R. J. et al., Genes Dev. 3:431-437 (1989); Dreyfuss G. et al., Trends Biochem. Sci. 13:86-91 (1988)).

Inside the putative RNA-binding domain there are two regions which are highly conserved. The first one is a hydrophobic segment of six residues (which is called the RNP-2 motif); the second one is an octapeptide motif (which is called RNP-1 or RNP-CS). The position of both motifs in the domain is shown in the following schematic representation:

Phosphatidylinositol-specific phospholipase C, Y Domain. One SEQ ID NO represents a polynucleotide encoding a novel member of the phosphatidylinositol-specific phospholipase C, Y domain family of proteins. Phosphatidylinositol-specific phospholipase C (EC3.1.4.11), a eukaryotic intracellular enzyme, plays an important role in signal transduction processes (Meldrum E. et al., Biochim. Biophys. Acta 1092:49-71 (1991)). It catalyzes the hydrolysis of 1-phosphatidyl-D-myo-inositol-3,4,5-triphosphate into the second messenger molecules diacylglycerol and inositol-1,4,5-triphosphate. This catalytic process is tightly regulated by reversible phosphorylation and binding of regulatory proteins (Rhee S. G., Choi K. D., Adv. Second Messenger Phosphoprotein Res. 26:35-61 (1992); Rhee S. G., Choi K. D., J. Biol. Chem. 267:12393-12396 (1992); Sternweis P. C., Smrcka A. V., Trends Biochem. Sci. 17:502-506 (1992)).

All eukaryotic PI-PLCs contain two regions of homology, referred to as “X-box” and “Y-box”. The order of these two regions is the same (NH2-X—Y—COOH), but the spacing is variable. In most isoforms, the distance between these two regions is only 50-100 residues but in the gamma isoforms one PH domain, two SH2 domains, and one SH3 domain are inserted between the two PLC-specific domains. The two conserved regions have been shown to be important for the catalytic activity. At the C-terminal of the Y-box, there is a C2 domain possibly involved in Ca-dependent membrane attachment.

Serine Carboxypeptidases. One SEQ ID NO represents a polynucleotide encoding a novel member of the serine carboxypeptidases family of proteins. Carboxypeptidases may be either metallo carboxypeptidases or serine carboxypeptidases (EC 3.4.16.5 and EC 3.4.16.6). The catalytic activity of the serine carboxypeptidases, like that of the trypsin family serine proteases, is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which is itself hydrogen-bonded to a serine (Liao D. I., Remington S. J., J. Biol. Chem. 265:6528-6531 (1990)).

dsrm Double-Stranded RNA Binding Motif. One SEQ ID NO represents a polynucleotide encoding a novel member of the dsrm double-stranded RNA binding motif proteins. In eukaryotic cells, a multitude of RNA-binding proteins play key roles in the posttranscriptional regulation of gene expression. Characterization of these proteins has led to the identification of several RNA-binding motifs. Several human and other vertebrate genetic disorders are caused by aberrant expression of RNA-binding proteins. (C. G. Burd & G. Dreyfuss, Science 265: 615-621 (1994)).

Proteins containing double stranded RNA binding motifs bind to specific RNA targets. Double stranded RNA binding motifs are exemplified by interferon-induced protein kinase in humans, which is part of the cellular response to dsRNA.

Some SEQ ID NOs encode members of the 4 trans-membrane integral membrane protein family. This family consists of type III proteins, which are integral membrane proteins that contain a N-terminal membrane-anchoring domain that is not cleaved during biosynthesis, and which functions as a translocation signal and a membrane anchor. The proteins also have three additional transmembrane regions.

One SEQ ID NO encodes a polypeptide having a calpain large subunit, domain III. Calpains are a family of intracellular proteases that play a variety of biological roles. Calpain 3, also known as p94, is predominantly expressed in skeletal muscle and plays a role in limb-girdle muscular dystrophy type 2A. (Sorimachi, H. et al., Biochem. J. 328:721-732, 1997).

Some SEQ ID NOs encode polypeptides having a C3HC4 type zinc finger domain (RING finger), which is a cysteine-rich domain of 40 to 60 residues that binds two atoms of zinc, and is believed to be involved in mediating protein-protein interactions. Mammalian proteins of this family include V(D)J recombination activating protein, which activates the rearrangement of immunoglobulin and T-cell receptor genes; breast cancer type 1 susceptibility protein (BRCA1); bmi-1 proto-oncogene; cbl proto-oncogene; and mel-18 protein, which is expressed in a variety of tumor cells and is a transcriptional repressor that recognizes and binds a specific DNA sequence.

One SEQ ID NO encodes a eukaryotic transcription factor with a fork head domain, of about 100 amino acid residues. Proteins of this group are transcription factors, including mammalian transcription factors HNF-3-alpha, -beta, and -gamma; interleukin-enhancer binding factor; and HTLF, which binds to a region of human T-cell leukemia virus long terminal repeat.

One SEQ ID NO encodes a polypeptide having a PDZ domain. Several dozen signaling proteins belong to this group of proteins that have 80-100 residue repeats known as PDZ domains. Several of the proteins interact with the C-terminal tetrapeptide motifs X-Ser/Thr/X-Val-COO- of ion channels and/or receptors. (Ponting, C. P., Protein Sci. 6; 464-468, 1997.)

One SEQ ID NO encodes a polypeptide in the family of phorbol esters/glycerol binding proteins. Phorbol esters (PE) are analogues of diacylglycerol (DAG) and potent tumor promoters. DAG activates a family of serine-threonine protein kinases, known as protein kinase C. The N-terminal region of protein kinase C binds PE and DAG, and contains one or two copies of a cysteine-rich domain of about 50 amino acid residues. Other proteins having this domain include diacylglycerol kinase; the vav oncogene; and N-chimaerin, a brain-specific protein. The DAG/PE binding domain binds two zinc ions through the six cysteines and two histidines that are conserved in the domain.

One SEQ ID NO encodes a polypeptide having a WW/rsp5/WWP domain. The protein is named for the presence of conserved aromatic positions, generally tryptophan, as well as a conserved proline. Proteins having the domain include dystrophin, vertebrate YAP protein, and IQGAP, a human GTPase activating protein which acts on ras.

One SEQ ID NO encodes a member of the dual specificity phosphatase family, having a catalytic domain, and some SEQ IDS NOs encode members of the protein tyrosine phosphatase family. These families are related and classified as tyrosine specific protein phosphatases. The enzymes catalyze the removal of a phosphate group from a tyrosine residue, and are important in the control of cell growth, proliferation, differentiation, and transformation.

TABLE 87 SEQ ID Start Stop Score Direction Description 9948 295 421 5872 For mkk like kinases 9949 31 182 3943 For Basic region plus leucine zipper transcription factors 9950 298 397 5625 For mkk like kinases 10105 175 395 7660 For SH2 Domain 10106 358 432 4320 For Ank repeat 10115 37 322 6049 For mkk like kinases 10153 23 121 4607 For SH3 Domain 10227 110 172 4150 For Zinc finger, C2H2 type 10329 42 191 4036 For Basic region plus leucine zipper transcription factors 10350 71 428 5538 Rev ATPases Associated with Various Cellular Activities 10471 116 288 3930 Rev Basic region plus leucine zipper transcription factors 10558 157 561 5797 For ATPases Associated with Various Cellular Activities 10665 209 427 5379 For Fibronectin type III domain 10687 116 288 3930 For Basic region plus leucine zipper transcription factors 10726 339 392 3620 For Zinc finger, C2H2 type 10739 341 406 2930 Rev EF-hand 10741 108 262 4179 For Basic region plus leucine zipper transcription factors 10755 158 353 4430 For Basic region plus leucine zipper transcription factors 11076 41 444 5279 Rev protein kinase 11111 186 416 5469 For Fibronectin type III domain 11187 238 315 3540 For Ank repeat 11188 79 240 11640 For LIM domain containing proteins 11207 73 234 3953 For Basic region plus leucine zipper transcription factors 11228 248 404 8226 for LIM domain containing proteins 11243 294 356 4690 for Zinc finger, C2H2 type 11244 1 234 8981 for C2 domain (prot. kinase C like) 11255 66 164 6390 for WD domain, G-beta repeats 11279 222 377 8686 for LIM domain containing proteins 11284 69 257 5221 for Basic region plus leucine zipper transcription factors 11299 42 140 7130 for WD domain, G-beta repeats 11305 243 398 8736 for LIM domain containing proteins 11329 222 350 10553 for Trypsin 11336 8 354 6073 for Protein Tyrosine Phosphatase 11373 49 209 3996 for Basic region plus leucine zipper transcription factors 11383 4 180 4978 for RNA recognition motif. (aka RRM, RBD, or RNP domain) 11397 54 437 5176 for protein kinase 11415 241 520 3929 for Helicases conserved C-terminal domain 11415 40 612 5187 for protein kinase 11422 154 216 4870 for Zinc finger, C2H2 type 11433 2 252 4662 for RNA recognition motif. (aka RRM, RBD, or RNP domain) 11446 156 212 3520 for Zinc finger, C2H2 type 11457 9 635 11087 for wnt family of developmental signaling proteins 11459 289 471 4107 for Basic region plus leucine zipper transcription factors 11468 200 391 4118 for Basic region plus leucine zipper transcription factors 11475 163 354 3958 for Basic region plus leucine zipper transcription factors 11476 207 398 4038 for Basic region plus leucine zipper transcription factors 11482 107 298 3978 for Basic region plus leucine zipper transcription factors 11541 180 365 4022 for Basic region plus leucine zipper transcription factors 11549 100 291 3998 for Basic region plus leucine zipper transcription factors 11593 196 258 4880 for Zinc finger, C2H2 type 11595 9 86 6610 for Homeobox Domain 11596 316 369 5780 rev Thioredoxins 11607 109 410 17414 for Ras family 11623 184 372 3977 for Basic region plus leucine zipper transcription factors 11626 92 439 24100 rev Phosphatidylinositol-specific phospholipase C, Y domain 11630 263 361 6400 for WD domain, G-beta repeats 11663 238 433 10572 rev Serine carboxypeptidases 11674 281 367 2580 for EF-hand 11681 236 334 5880 for WD domain, G-beta repeats 11698 64 126 4790 for Zinc finger, C2H2 type. 11720 295 351 4030 for Zinc finger, C2H2 type 11723 301 378 3460 for Ank repeat 11727 36 161 4170 for Basic region plus leucine zipper transcription factors 11730 184 315 8390 for N-terminal homology in Ets domain 11733 127 294 10770 for Bromodomain (conserved sequence found in human, Drosophila and yeast proteins.) 11737 9 146 4741 for Double-stranded RNA binding motif 11738 278 355 3460 for Ank repeat 11739 123 299 12150 for Homeobox Domain 11740 127 303 12180 for Homeobox Domain 11749 184 267 4270 for Ank repeat 11751 18 173 8987 for SH3 Domain 11754 51 206 8987 for SH3 Domain 11758 224 307 4270 for Ank repeat 11765 12 398 36700 for G-protein alpha subunit 11828 160 258 6370 for WD domain, G-beta repeats 11830 35 151 9335 for Zinc finger, C3HC4 type (RING finger) 11899 60 197 7917 for Zinc finger, C3HC4 type (RING finger) 11984 253 306 5410 for Zinc finger, CCHC class 12054 2 401 10596 for ATPases Associated with Various Cellular Activities 12135 90 179 5380 for WW/rsp5/WWP domain containing proteins 12137 127 225 5500 for WD domain, G-beta repeats 12200 20 387 6044 for Protein Tyrosine Phosphatase 12201 183 353 5136 for C2 domain (prot. kinase C like) 12205 12 382 5228 for protein kinase 12229 20 371 5962 for Protein Tyrosine Phosphatase 12282 48 211 4132 for Basic region plus leucine zipper transcription factors 12343 43 194 3996 for Basic region plus leucine zipper transcription factors 12347 25 350 4675 for Dual specificity phosphatase, catalytic domain 12481 18 101 4560 for Ank repeat 12496 0 311 10295 for 4 transmembrane segments integral membrane proteins 12510 60 165 4560 for SH2 Domain 12603 9 461 5759 for ATPases Associated with Various Cellular Activities 12745 116 400 16107 for DEAD and DEAH box helicases 12778 100 320 5550 rev ATPases Associated with Various Cellular Activities 12790 198 392 9384 for DEAD and DEAH box helicases 12863 18 281 10480 for Calpain large subunit, domain III 12888 5 387 5976 rev protein kinase 12934 131 214 3600 for Ank repeat 12966 191 292 5295 for WD domain, G-beta repeats 13000 190 252 4360 for Zinc finger, C2H2 type 13027 275 367 5791 for WD domain, G-beta repeats 13066 190 369 4022 for Basic region plus leucine zipper transcription factors 13071 129 320 3947 for Basic region plus leucine zipper transcription factors 13077 167 334 4180 for Basic region plus leucine zipper transcription factors 13094 14 164 5951 for mkk like kinases 13094 8 112 5968 for protein kinase 13097 45 386 19398 for ATPases Associated with Various Cellular Activities 13102 14 215 9133 for 4 transmembrane segments integral membrane proteins 13109 229 390 6089 for mkk like kinases 13109 118 390 8063 for protein kinase 13112 293 355 3570 for Zinc finger, C2H2 type 13114 0 215 10146 for 4 transmembrane segments integral membrane proteins 13116 281 343 4490 for Zinc finger, C2H2 type 13127 34 256 4190 for Basic region plus leucine zipper transcription factors 13177 138 394 9877 for Ras family 13185 8 139 9328 for ATPases Associated with Various Cellular Activities 13186 97 180 3820 for Ank repeat 13193 11 187 15442 for Fork head domain, eukaryotic transcription factors 13200 15 182 9681 for mkk like kinases 13204 16 102 4680 for EF-hand 13211 208 300 5585 for WD domain, G-beta repeats. 13216 7 153 6100 for Helicases conserved C-terminal domain 13225 161 223 4900 for Zinc finger, C2H2 type 13226 43 321 8740 for SH2 Domain 1 3258 94 342 14970 for SH2 Domain 13264 65 271 12512 for PDZ domain 13270 124 270 6068 for Phorbol esters/diacylglycerol binding

Example 58 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 88 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepare the cDNA library, the abbreviated name of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 88 Description of cDNA Libraries Number of Clones in Library this (lib #) Description Clustering 1 Km12 L4 307133 Human Colon Cell Line, High Metastatic Potential (derived from Km12C) “High Colon” 2 Km12C 284755 Human Colon Cell Line, Low Metastatic Potential “Low Colon” 3 MDA-MB-231 326937 Human Breast Cancer Cell Line, High Metastatic Potential; micro-metastases in lung “High Breast” 4 MCF7 318979 Human Breast Cancer Cell, Non Metastatic “Low Breast” 8 MV-522 223620 Human Lung Cancer Cell Line, High Metastatic Potential “High Lung” 9 UCP-3 312503 Human Lung Cancer Cell Line, Low Metastatic Potential “Low Lung” 12 Human microvascular endothelial cells (HMEC) - 41938 Untreated PCR (OligodT) cDNA library 13 Human microvascular endothelial cells (HMEC) - 42100 Basic fibroblast growth factor (bFGF) treated PCR (OligodT) cDNA library 14 Human microvascular endothelial cells (HMEC) - 42825 Vascular endothelial growth factor (VEGF) treated PCR (OligodT) cDNA library 15 Normal Colon - UC#2 Patient 34285 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 16 Colon Tumor - UC#2 Patient 35625 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 17 Liver Metastasis from Colon Tumor of UC#2 36984 Patient PCR (OligodT) cDNA library “High Colon Metastasis Tissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT) cDNA library “Normal Colon Tumor Tissue” 19 Colon Tumor - UC#3 Patient 41388 PCR (OligodT) cDNA library “High Colon Tumor Tissue” 20 Liver Metastasis from Colon Tumor of UC#3 30956 Patient PCR (OligodT) cDNA library “High Colon Metastasis Tissue” 21 G RRpz 164801 Human Prostate Cell Line 22 WOca 162088 Human Prostate Cancer Cell Line

The KM12L4 and KM12C cell lines are described in Example 55 above. The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz cell line refers to low passage (3 passages or fewer) human prostate cells, and the WOca cell line refers to low passage (3 passages or fewer) human prostate cancer cells.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974)).

Example 59 Polynucleotides Differentially Expressed in High Metastatic Potential Breast Cancer Cells Versus Low Metastatic Breast Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential breast cancer tissue and low metastatic breast cancer cells. Expression of these sequences in breast cancer can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic maker, for risk assessment, patient treatment and the like. These polynucleotide sequence can also be used in combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential breast cancer cells and low metastatic potential breast cancer cells.

TABLE 89 Differentially expressed polynucleotides: Higher expression in high metastatic potential breast cancer (lib3) relative to low metastatic breast cancer cells (lib4) SEQ ID NOs: Lib3 clones Lib4 clones lib3/lib4 472 64 0 62 11770 6 0 6 11775 8 0 8 11786 6 0 6 11791 6 0 6 11794 12 3 4 11842 89 22 4 12037 7 0 7 12038 7 0 7 12054 37 13 3 12109 19 0 19 12112 16 5 3 12151 12 2 6 12158 6 0 6 12257 21 2 10 12297 16 4 4 12313 6 0 6 12314 6 0 6 12409 13 3 4 12424 16 2 8 12459 8 1 8 12461 11 1 11 12526 11 2 5 12559 22 5 4 12593 8 0 8 12598 19 0 19 12603 14 4 3 12626 8 0 8 12643 9 0 9 12676 6 0 6 12695 10 0 10 12723 13 2 6 12737 6 0 6 12825 14 0 14 12878 26 8 3 12883 17 4 4 12887 6 0 6 12896 22 3 7 12899 13 1 13 12929 6 0 6 12962 10 1 10 12990 33 12 3 12991 9 1 9 13014 19 3 6 13016 11 2 5 13092 12 2 6 13122 8 1 8 13129 27 8 3 13131 13 1 13 13203 8 0 8 13207 6 0 6 13250 14 3 5 13254 13 1 13

TABLE 90 Differentially expressed polynucleotides: Higher expression in low metastatic breast cancer cells (lib4) relative to high metastatic potential breast cancer (lib3) SEQ ID Lib 3 Lib 4 NOs: Clones Clones lib4/lib3 10321 0 6 6 10533 3 21 7 10543 0 6 6 10545 0 8 8 10631 0 9 9 10663 0 7 7 11244 2 29 15 11371 2 13 7 11799 0 9 9 11834 0 7 7 11870 0 6 6 11874 8 32 4 11934 0 7 7 11965 0 7 7 11995 1 22 23 12006 0 6 6 12043 0 9 9 12064 0 8 8 12081 0 6 6 12082 0 12 12 12083 5 19 4 12091 2 15 8 12111 5 16 3 12163 20 43 2 12185 3 18 6 12232 24 56 2 12265 1 13 13 12274 0 10 10 12290 0 6 6 12312 1 17 17 12323 1 21 22 12362 0 6 6 12379 0 11 11 12442 0 6 6 12494 1 10 10 12497 0 6 6 12503 1 17 17 12509 0 6 6 12528 1 9 9 12551 5 24 5 12633 5 24 5 12647 0 6 6 12671 1 14 14 12713 4 15 4 12745 0 7 7 12906 5 15 3 12924 1 14 14 12928 20 58 3 12966 4 17 4 12976 2 17 9 12994 2 11 6 12995 0 6 6 13021 0 6 6 13047 15 52 4 13051 15 52 4 13061 0 6 6 13106 22 49 2 13172 23 96 4 13201 19 46 2 13204 20 40 2 13265 0 9 9

Example 60 Polynucleotides Differentially Expressed in High Metastatic Potential Lung Cancer Cells Versus Low Metastatic Lung Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential lung cancer cells and low metastatic lung cancer cells. Expression of these sequences in lung cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential lung cancer cells and low metastatic potential lung cancer cells:

TABLE 91 Differentially expressed polynucleotides: Higher expression in high metastatic potential lung cancer cells (lib8) relative to low metastatic lung cancer cells (lib9) SEQ ID NO: Lib8 clones Lib9 clones lib8/lib9 9933 10 0 10 10056 5 0 5 10070 5 0 7 10071 9 0 13 10090 6 0 8 10119 10 0 14 10173 5 0 7 10181 5 0 7 10190 5 0 7 10267 6 1 8 10331 5 0 7 10426 5 0 7 10439 6 0 8 10449 5 0 7 10507 5 0 7 10542 7 0 10 10556 7 0 10 10579 5 0 7 10597 8 0 11 10599 5 0 7 10619 9 2 6 10633 28 13 3 10693 11 0 15 10731 5 0 7 10753 8 2 6 10820 11 2 8 11087 5 0 7 11252 6 0 8 11271 5 0 7 11443 11 1 15 11625 5 0 7 11671 17 9 3 11687 20 4 7 11688 5 0 7 11699 6 0 8 11700 40 3 19 11718 6 1 8 11722 6 1 8 11730 16 9 2 11803 6 0 8 11838 8 1 11 11858 6 0 8 11894 43 9 7 11943 12 1 17 11964 8 1 11 11979 20 13 2 11990 16 4 6 12047 5 0 7 12096 10 2 7 12100 44 13 5 12103 11 1 15 12104 10 4 3 12202 7 0 10 12230 10 4 3 12233 10 0 14 12312 14 6 3 12317 6 1 8 12379 10 4 3 12433 6 0 8 12516 5 0 7 12576 8 2 6 12588 6 1 8 12589 6 1 8 12966 21 3 10 12969 16 5 4 13011 7 1 10 13059 181 119 2 13076 5 0 7 13106 16 5 4 13129 5 0 7 13139 28 4 10 13155 7 1 10 13168 16 0 22 13183 8 2 6 13224 7 0 10 13228 20 0 28 13237 24 4 8 13249 5 0 7 13250 5 0 7

TABLE 92 Differentially expressed polynucleotides: Higher expression in low metastatic lung cancer cells (lib 9) relative to high metastatic potential lung cancer cells (lib 8) SEQ ID NO: Lib 8 clones Lib 9 clones lib 9/lib 8 9943 3 20 5 9972 0 18 13 9983 0 8 6 9989 0 11 8 10024 10 66 5 10048 0 16 11 10133 1 14 10 10152 4 35 6 10156 0 13 9 10183 0 29 21 10248 2 17 6 10287 1 37 26 10289 0 11 8 10337 0 8 6 10369 0 9 6 10380 0 9 6 10403 0 26 19 10413 0 41 29 10436 1 12 9 10441 1 11 8 10500 1 17 12 10533 3 23 5 10625 0 11 8 10645 5 23 3 10725 0 14 10 10743 0 9 6 10755 1 14 10 10793 0 12 9 10819 5 21 3 10936 2 14 5 11063 0 8 6 11073 0 12 9 11085 2 45 16 11089 1 13 9 11221 2 13 5 11245 1 13 9 11246 1 13 9 11286 0 12 9 11296 0 12 9 11356 2 18 6 11361 1 14 10 11385 0 13 9 11395 0 13 9 11414 0 8 6 11415 1 13 9 11583 38 253 5 11601 1 17 12 11606 0 9 6 11677 0 8 6 11736 4 18 3 11756 3 16 4 11764 3 23 5 11775 2 17 6 11829 1 18 13 12065 2 16 9 12075 0 9 6 12382 0 12 9 12643 10 38 3 12668 403 2000 4 12720 6 25 3 12912 3 18 4 12999 0 10 7 13026 3 23 5 13211 0 20 14 13243 110 548 4

Example 61 Polynucleotides Differentially Expressed in High Metastatic Potential Colon Cancer Cells Versus Low Metastatic Colon Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential colon cancer cells and low metastatic colon cancer cells. Expression of these sequences in colon cancer tissue can provide diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the metastatic process. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment. In another example, sequences that display higher expression in the low metastatic potential cells can be associated with genes or regulatory sequences that inhibit metastasis, and thus the expression of these polynucleotides in a sample may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following table summarizes identified polynucleotides with differential expression between high metastatic potential colon cancer cells and low metastatic potential colon cancer cells:

TABLE 93 Differentially expressed polynucleotides: Higher expression in low metastatic colon cancer cells (lib 2) relative to high metastatic potential colon cancer cells (lib 1) SEQ ID NOs: Lib 1 clones Lib 2 clones lib 2/lib 1 10348 0 9 10 11413 0 8 9 11842 34 114 4 11905 3 12 4 11937 0 9 10 11955 2 10 5 11968 8 25 3 12054 24 87 4 12065 2 16 9 12127 6 27 5 12134 2 11 6 12158 1 10 11 12226 2 12 6 12232 28 62 2 12276 5 14 3 12279 3 21 8 12281 0 6 6 12297 3 12 4 12488 3 20 7 12490 0 6 6 12507 54 172 3 12511 15 41 3 12530 0 6 6 12555 0 9 10 12560 7 20 3 12569 0 9 10 12581 0 9 10 12593 4 13 4 12601 0 6 6 12621 9 25 3 12623 8 23 3 12634 2 12 6 12723 9 22 3 12740 13 29 2 12759 1 8 9 12765 2 15 8 12785 0 6 6 12825 0 6 6 12834 44 109 3 12852 0 6 6 12854 5 16 3 12876 1 11 12 12878 3 27 10 12896 16 30 2 12899 12 27 2 12919 2 13 7 12928 12 29 3 13034 0 7 8 13075 502 2170 5 13129 2 21 11 13130 0 9 10 13132 0 7 8 13154 2 12 6 13170 2 12 6 13215 3 12 4 13254 1 8 9

Example 62 Polynucleotides Differentially Expressed in High Metastatic Potential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high metastatic potential colon cancer tissue and normal tissue. Expression of these sequences in colon cancer tissue can provide diagnostic, prognostic and/or treatment information. For example, sequences that are highly expressed in the high metastatic potential cells can be indicative of increased expression of genes or regulatory sequences involved in the advanced disease state which involves processes such as angiogenesis, differentiation, cell replication, and metastasis. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant more aggressive treatment.

The differential expression of these polynucleotides can be used as a diagnostic marker, a prognostic marker, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential colon cancer tissue and normal colon tissue:

TABLE 94 Differentially expressed polynucleotides isolated from samples from two patients (patient 2 and patient 3 and): Lower expression in high metastatic potential colon tissue (patient 2: lib 17; patient 3: lib 20) vs. normal colon tissue (patient 2: lib 15; patient 3: lib 18) SEQ ID NO: lib 15 clones lib 17 clones lib 15/lib 17  9988 19 7 3 10042 6 0 6 10059 24 8 3 10116 6 0 6 10117 113 0 121 10173 28 9 3 10331 28 9 3 10431 11 1 12 10560 17 7 3 10561 7 0 8 10873 12 3 4 10930 209 16 14 10943 8 0 9 10959 12 3 4 10974 26 7 4 11025 31 15 2 11044 17 0 18 11048 17 0 18 11057 109 0 117 11163 14 1 15 11172 73 0 78 11202 34 7 5 11204 34 7 5 11258 13 4 3 11393 73 0 78 11424 18 3 6 11472 68 6 12 11473 2542 14 195 11524 2542 14 195 11547 6 0 6 11562 142 4 38 11672 12 0 10 11683 13 0 14 SEQ ID NO: Lib18 Clones Lib20 Clones lib18/lib20 10024 28 11 2 10117 21 0 18 10173 9 0 8 10331 9 0 8 10930 11 1 9 11057 14 0 12 11172 23 0 20 11562 18 0 15 11683 12 0 10 13075 140 43 3

TABLE 95 Differentially expressed polynucleotides isolated from samples from two patients (patient 2 and patient 3): Lower expression in normal colon tissue (patient 2: lib 15; patient 3: lib 18)vs. high metastatic potential colon tissue (patient 2: lib 17; patient 3: lib 20). SEQ ID NO: Lib 15 Clones Lib 17 Clones lib 17/lib 15 10240 3 23 7 10282 1 9 8 10755 21 99 4 10778 6 20 3 10804 13 28 2 10835 13 28 2 10900 2 11 5 11145 8 70 8 11227 0 8 7 11236 29 84 3 11348 27 127 4 11361 0 9 8 11453 1 12 11 11459 12 43 3 11471 0 7 7 11475 1 9 8 11476 1 9 8 11488 2189 5122 2 11490 6 18 3 11495 3 25 8 11500 4 22 5 11520 25 157 6 11532 9 48 5 11535 15 61 4 11539 2 17 8 11541 4 99 23 11545 6 35 5 11566 4 22 5 11583 4 28 7 11602 2 18 8 11623 3 15 5 11719 0 7 7 12668 23 60 2 12703 4 14 3 12724 1 9 8 12895 3 14 4 13047 18 57 3 13048 26 124 4 13065 64 210 3 13069 940 2267 2 13070 2 15 7 SEQ ID NO: lib 18 clones lib 20 clones lib 20/lib 18 10784 0 5 6 11488 1 7 8 11499 1 7 8 11509 1 7 8 12709 0 5 6

Example 63 Polynucleotides Differentially Expressed in High Colon Tumor Potential Patient Tissue Versus Metastasized Colon Cancer Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from colon cancer tissue and cells derived from colon cancer tissue metastases to liver. Expression of these sequences in colon cancer tissue can provide diagnostic, prognostic and/or treatment information associated with the transformation of precancerous tissue to malignant tissue. This information can be useful in the prevention of achieving the advanced malignant state in these tissues, and can be important in risk assessment for a patient.

The following table summarizes identified polynucleotides with differential expression between high tumor potential colon cancer tissue and cells derived from high metastatic potential colon cancer cells:

TABLE 96 Differentially expressed polynucleotides: Greater expression in metastatic colon tumor tissue (lib 20) vs. colon tumor tissue (lib 19) SEQ ID NO: lib 19 clones lib 20 clones lib 20/lib 19 10856 0 6 8 10895 0 5 7 11439 1 8 11 11465 1 11 15 11469 1 11 15 11493 1 8 11 11499 0 7 9 11509 0 7 9 11518 8 21 4 11526 158 632 5 11541 1 7 9

TABLE 97 Greater expression in colon tumor tissue (lib 19) than metastatic colon tissue (lib 20) SEQ ID NO: lib 19 clones lib 20 clones lib 19/lib 20 10024 64 11 4 10930 53 1 40 11145 18 4 3 11490 8 0 6 11645 15 3 4 11730 17 2 6 12668 47 6 6 13065 19 2 7 13243 20 1 15

Example 64 Polynucleotides Differentially Expressed in High Tumor Potential Colon Cancer Patient Tissue Versus Normal Patient Tissue

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from high tumor potential colon cancer tissue and normal tissue. Expression of these sequences in colon cancer tissue can provide diagnostic, prognostic and/or treatment information associated with the prevention of the malignant state in these tissues, and can be important in risk assessment for a patient. For example, sequences that are highly expressed in the potential colon cancer cells are associated with or can be indicative of increased expression of genes or regulatory sequences involved in early tumor progression. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The following tables summarize polynucleotides that are differentially expressed between high metastatic potential colon cancer cells and normal colon cells:

TABLE 98 Differentially expressed polynucleotides detected in samples from patient (patient 2) Higher expression in normal colon tissue (patient 2, lib 15) vs. tumor potential colon tissue (patient 2: lib 16) SEQ ID NO: lib 15 clones lib 16 clones lib 16/lib 15 9988 19 7 3 10024 116 54 2 10059 24 4 6 10116 6 0 6 10117 113 3 40 10173 28 6 5 10331 28 6 5 10561 7 0 7 10749 10 2 5 10857 31 13 3 10930 209 37 6 11014 12 3 4 11044 17 0 18 11048 17 0 18 11057 109 1 115 11172 73 1 77 11202 34 13 3 11204 34 13 3 11258 13 3 5 11372 11 3 4 11393 73 1 77 11424 18 6 3 11473 2542 448 6 11524 2542 448 6 11533 36 14 3 11549 24 9 3 11562 142 2 75 11565 39 14 3 11568 24 8 3 11596 19 6 3 11672 13 0 14 11683 13 0 14 11685 177 65 3 11691 24 8 3

TABLE 99 Differentially expressed polypeptides detected in samples from patient. Lower expression in normal colon tissue (lib 18) than colon tumor tissue (lib 19) SEQ ID NO: lib 18 clones lib 19 clones lib 19/lib 18 13065 3 19 6 13069 21 228 10 13243 3 20 6

TABLE 100 Differentially expressed polypeptides detected in samples from patient. Higher expression in normal colon tissue (lib 18) than colon tumor tissue (lib 19) SEQ ID NO: lib 18 clones lib 19 clones lib 18/lib 19 10117 21 2 12 10384 6 0 7 10408 6 0 7 10664 6 0 7 10778 11 2 6 10895 7 0 8 10930 209 37 6 10964 8 1 9 11057 14 0 16 11172 23 0 26 11311 16 4 5 11393 23 0 26 11508 6 0 7 11510 22 11 2 11526 386 158 3 11562 18 0 21 11672 12 0 14 11683 12 0 14 lib 19/lib 18 10024 28 64 2 10930 11 53 4 11145 2 18 8 11170 6 19 3 11478 1 9 8 11490 0 8 7 11527 1 9 8 11685 2 13 6 11701 1 9 8 11730 1 17 15

TABLE 101 Differentially expressed polynucleotides: Higher expression in colon tumor tissue (patient 2, lib 16) vs. normal colon tissue (patient 2, lib 15) SEQ ID NO: lib 15 clones lib 16 clones lib 16/lib 15 9926 1 9 9 10083 6 19 3 10653 4 15 4 10755 21 53 2 10847 2 11 5 10884 2 11 5 10906 2 11 5 10945 7 19 3 10963 4 16 4 11038 4 16 4 11145 8 46 5 11146 0 9 9 11170 7 95 13 11235 0 6 6 11348 27 81 3 11361 0 9 9 11459 12 28 2 11472 68 590 8 11479 4 24 6 11496 1 10 9 11507 5 20 4 11529 3 13 4 11539 2 23 11 11545 6 23 4 11592 2 15 7 12335 0 7 7 12668 23 54 2 12895 3 14 4 13048 26 64 2 13051 18 54 3

Example 65 Polynucleotides Differentially Expressed in Growth Factor-Stimulated Human Microvascular Endothelial Cells (HMEC) Relative to Untreated HMEC

A number of polynucleotide sequences have been identified that are differentially expressed between human microvascular endothelial cells (HMEC) that have been treated with growth factors relative to untreated HMEC.

Sequences that are differentially expressed between growth factor-treated HMEC and untreated HMEC can represent sequences encoding gene products involved in angiogenesis, metastasis (cell migration), and other developmental and oncogenic processes. For example, sequences that are more highly expressed in HMEC treated with growth factors (such as bFGF or VEGF) relative to untreated HMEC can serve as markers of cancer cells of higher metastatic potential. Detection of expression of these sequences in colon cancer tissue can provide diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The following table summarizes identified polynucleotides with differential expression between growth factor-treated and untreated HMEC.

TABLE 102 Differentially expressed polynucleotides: SEQ ID NO: lib 12 clones lib 13 clones lib 12/lib 13 Higher expression in untreated HMEC (lib 12) vs. bFGF treated HMEC (lib 13) 10768 6 0 6 10978 6 0 6 11125 12 2 6 13127 12 0 12 Lower expression in untreated HMEC (lib 12) vs. bFGF treated HMEC (lib 13) 12667 3 12 4 13244 0 6 6

TABLE 103 Differentially expressed polynucleotides: SEQ ID NO: lib 12 clones lib 14 clones lib 12/lib 14 Higher expression in untreated HMEC (lib 12) VEGF treated HMEC (lib14) 11069 9 0 9 Lower expression in untreated HMEC (lib 12) vs. VEGF treated HMEC (lib14) 13243 22 50 2

Example 66 Polynucleotides Differentially Expressed in Normal Prostate Cells Relative to Prostate Cancer Cells

A number of polynucleotide sequences have been identified that are differentially expressed between cells derived from normal prostate cells and prostate cancer cells. Expression of these sequences prostate tissue suspected of being cancerous can provide diagnostic, prognostic and/or treatment information. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers. The following table summarizes identified polynucleotides with differential expression between high metastatic potential colon cancer cells and low metastatic potential colon cancer cells:

TABLE 104 Differentially expressed polynucleotides: normal prostate cell line (lib 21) vs. prostate cancer cell line (lib 22) SEQ ID NO: lib 21 clones lib 22 clones lib 21/lib 22 Higher in lib 21 9972 17 2 8 11673 22 8 3 11720 7 0 7 11764 22 6 4 10365 8 0 8 11329 6 0 6 11979 18 6 3 12062 12 3 4 12551 13 1 13 12818 16 2 8 13257 12 2 6 Higher in lib 22 10005 2 13 7 10012 0 9 9 10606 0 9 9 11188 1 15 15 11500 25 74 3 11566 25 74 3 11568 12 27 2 11629 5 16 3 11636 5 16 3 11691 12 27 2 11879 0 6 6 12906 0 6 6 13047 13 42 3 13051 13 42 3 13069 263 962 4 13141 0 6 6 13187 0 6 6

Example 67 Polynucleotides Differentially Expressed Across Multiple Libraries

A number of polynucleotide sequences have been identified that are differentially expressed between cancerous cells and normal cells across two or more tissue types tested (i.e., breast, colon, lung, and prostate). Expression of these sequences in a tissue of any origin can provide diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. These polynucleotides can also serve as non-tissue specific markers of, for example, risk of metastasis of a tumor. The following polynucleotides were differentially expressed but without tissue type-specificity in at least two of the breast, colon, lung, and prostate libraries tested: 9972, 10024, 10274, 10331, 10533, 10755, 11361, 11500, 11566, 11568, 11583, 11691, 11701, 11730, 11764, 11775, 11794, 11842, 11979, 11990, 12054, 12065, 12158, 12232, 12297, 12312, 12335, 12379, 12409, 12551, 12593, 12623, 12643, 12668, 12703, 12723, 12878, 12895, 12896, 12899, 12906, 12928, 12966, 13047, 13048, 13051, 13065, 13069, 13075, 13129, 13243, 13250 and 13254.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Deposit Information:

The following materials were deposited with the American Type Culture Collection (ATCC); CMCC=Chiron Master Culture Collection:

cDNA Libraries Deposited with ATCC ATCC CMCC Tube Number Deposit Date Accession No. Accession No. ES137 May 30, 2000 ES138 May 30, 2000 ES139 May 30, 2000 ES140 May 30, 2000 ES141 May 30, 2000 ES142 May 30, 2000 ES143 May 30, 2000 ES137 May 30, 2000 ES144 May 30, 2000 ES145 May 30, 2000 ES146 May 30, 2000 ES147 May 30, 2000 ES148 May 30, 2000 ES149 May 30, 2000 ES150 May 30, 2000 ES151 May 30, 2000 ES152 May 30, 2000 ES153 May 30, 2000 ES154 May 30, 2000 ES155 May 30, 2000 ES156 May 30, 2000 ES157 May 30, 2000 ES158 May 30, 2000 ES159 May 30, 2000 ES160 May 30, 2000 ES161 May 30, 2000 ES162 May 30, 2000 ES163 May 30, 2000 ES164 May 30, 2000 ES165 May 30, 2000 ES166 May 30, 2000 ES167 May 30, 2000

Table 105 lists the clones for each deposit, designated as “tube” number. This deposit is provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones

Where the ATCC deposit is composed of a pool of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

TABLE 105 Clone Name Tube M00001351A:B02 ES 137 M00001356A:H11 ES 137 M00001363D:D09 ES 137 M00001395D:H02 ES 137 M00001439C:H06 ES 137 M00001476B:G10 ES 137 M00001582A:E02 ES 137 M00003750D:E06 ES 137 M00003761C:F02 ES 137 M00003770A:E05 ES 137 M00003786A:A11 ES 137 M00003800A:F09 ES 137 M00003816D:E11 ES 137 M00003902A:C03 ES 137 M00003991C:F06 ES 137 M00003995B:E03 ES 137 M00004046C:A08 ES 137 M00004105D:D05 ES 137 M00004139B:B10 ES 137 M00004140D:C03 ES 137 M00004144A:H05 ES 137 M00004152A:C12 ES 137 M00004155D:A10 ES 137 M00004168A:G11 ES 137 M00004197B:H10 ES 137 M00004222C:E03 ES 137 M00004234A:E07 ES 137 M00004239B:F11 ES 137 M00004241B:H07 ES 137 M00004264B:A05 ES 137 M00004278A:F09 ES 137 M00004282D:C11 ES 137 M00004308C:C06 ES 137 M00004340C:C07 ES 137 M00004354D:E05 ES 137 M00004361A:H02 ES 137 M00004372B:F07 ES 137 M00004378A:B10 ES 137 M00004393B:E07 ES 137 M00023282A:C02 ES 137 M00023300D:C11 ES 137 M00023316C:G08 ES 137 M00023333D:C12 ES 137 M00023352B:F03 ES 137 M00023352D:H03 ES 137 M00023376B:G04 ES 137 M00023377B:F01 ES 137 M00023398B:D12 ES 137 M00023399C:E10 ES 137 M00026803A:F08 ES 137 M00026843B:D10 ES 137 M00026850D:F09 ES 137 M00026851B:F01 ES 137 M00026856D:F02 ES 137 M00026857D:G12 ES 137 M00026859D:D01 ES 137 M00026860B:C05 ES 137 M00026865B:A06 ES 137 M00026868C:E11 ES 137 M00026878A:F05 ES 137 M00026882D:G09 ES 137 M00026885A:H09 ES 137 M00026901A:G07 ES 137 M00026914A:H10 ES 137 M00026915B:C06 ES 137 M00026918B:D01 ES 137 M00026922C:B02 ES 137 M00026922C:G03 ES 137 M00026926A:E10 ES 137 M00026927D:F02 ES 137 M00026928D:A03 ES 137 M00026935C:B04 ES 137 M00026941D:A04 ES 137 M00026944B:E03 ES 137 M00026946A:F12 ES 137 M00026980A:D09 ES 137 M00027016A:B06 ES 137 M00027018A:C09 ES 137 M00027021A:G02 ES 137 M00027022D:G11 ES 137 M00027030C:H06 ES 137 M00027035D:C06 ES 137 M00027049B:F05 ES 137 M00027078A:B02 ES 137 M00027080A:B01 ES 137 M00027085C:E11 ES 137 M00027094A:B03 ES 137 M00027103B:A09 ES 137 M00027108C:B03 ES 137 M00027121D:C05 ES 137 M00027135A:B11 ES 137 M00027136C:C09 ES 137 M00027141C:H03 ES 137 M00027159D:F03 ES 137 M00027162B:F05 ES 137 M00027178B:G09 ES 137 M00027179D:E06 ES 138 M00027181D:A05 ES 138 M00027195C:E04 ES 138 M00027198B:B08 ES 138 M00027200A:F02 ES 138 M00027207B:F07 ES 138 M00027212D:E03 ES 138 M00027228D:A01 ES 138 M00027232D:B08 ES 138 M00027233B:C01 ES 138 M00027236A:E04 ES 138 M00027237C:B08 ES 138 M00027248A:C02 ES 138 M00027256B:H09 ES 138 M00027258A:A07 ES 138 M00027263A:F10 ES 138 M00027292D:F10 ES 138 M00027297A:C04 ES 138 M00027299B:B12 ES 138 M00027301A:G05 ES 138 M00027301B:B08 ES 138 M00027314C:D09 ES 138 M00027319D:B11 ES 138 M00027324D:C05 ES 138 M00027347C:G07 ES 138 M00027355A:B07 ES 138 M00027359B:G05 ES 138 M00027366A:F11 ES 138 M00027379C:B07 ES 138 M00027392B:H02 ES 138 M00027396D:G08 ES 138 M00027398C:F07 ES 138 M00027438C:G07 ES 138 M00027462A:D07 ES 138 M00027462B:H07 ES 138 M00027468A:C09 ES 138 M00027475B:E10 ES 138 M00027476A:C09 ES 138 M00027486A:F06 ES 138 M00027520A:C05 ES 138 M00027525B:D06 ES 138 M00027526D:F03 ES 138 M00027528C:B10 ES 138 M00027537C:B01 ES 138 M00027546C:B10 ES 138 M00027591B:C04 ES 138 M00027596A:A10 ES 138 M00027596C:E06 ES 138 M00027602B:C01 ES 138 M00027615A:F10 ES 138 M00027617B:C12 ES 138 M00027620D:F11 ES 138 M00027625A:H01 ES 138 M00027634A:D11 ES 138 M00027641C:A03 ES 138 M00027647C:D03 ES 138 M00027652B:F11 ES 138 M00027668C:H12 ES 138 M00027729D:H06 ES 138 M00027733A:A02 ES 138 M00027741B:F09 ES 138 M00027743A:C03 ES 138 M00027801C:C11 ES 138 M00027813C:F01 ES 138 M00027818C:C07 ES 138 M00027836D:F12 ES 138 M00027837C:D09 ES 138 M00028120D:F12 ES 138 M00028066C:D07 ES 138 M00028184D:G10 ES 138 M00028185B:A06 ES 138 M00028196D:A03 ES 138 M00028201B:H12 ES 138 M00028207D:E09 ES 138 M00028210B:D02 ES 138 M00028212C:B08 ES 138 M00028215D:F03 ES 138 M00028220A:B04 ES 138 M00028314D:F05 ES 138 M00028316B:H12 ES 138 M00028354A:B12 ES 138 M00028354D:A03 ES 138 M00028357A:G10 ES 138 M00028362A:G11 ES 138 M00028364C:G08 ES 138 M00028369D:E08 ES 138 M00028617C:A12 ES 138 M00028768C:D05 ES 138 M00028770A:D04 ES 138 M00028772C:B09 ES 138 M00028775D:F03 ES 138 M00028777B:G12 ES 138 M00031368A:E10 ES 138 M00031417C:G09 ES 138 M00031419D:C04 ES 138 M00031485D:G02 ES 138 M00032480B:E10 ES 139 M00032492A:C01 ES 139 M00032495B:D02 ES 139 M00032499C:A01 ES 139 M00032508B:H03 ES 139 M00032510D:F12 ES 139 M00032510D:G06 ES 139 M00032513D:F01 ES 139 M00032530D:C02 ES 139 M00032535D:H01 ES 139 M00032539B:C11 ES 139 M00032540A:A09 ES 139 M00032541D:H08 ES 139 M00032545B:H09 ES 139 M00032545D:G05 ES 139 M00032550D:C02 ES 139 M00032551B:G05 ES 139 M00032577A:C04 ES 139 M00032578A:G06 ES 139 M00032584A:H08 ES 139 M00032592A:H11 ES 139 M00032597C:B01 ES 139 M00032638C:G08 ES 139 M00032638D:A06 ES 139 M00032668D:G12 ES 139 M00032678C:D06 ES 139 M00032688D:D11 ES 139 M00032712B:G02 ES 139 M00032724A:C05 ES 139 M00032725C:F06 ES 139 M00032726C:C01 ES 139 M00032731B:C10 ES 139 M00032731C:C07 ES 139 M00032737B:E09 ES 139 M00032739A:A06 ES 139 M00032744B:F10 ES 139 M00032766B:D12 ES 139 M00032766C:A04 ES 139 M00032790B:A07 ES 139 M00032793A:F06 ES 139 M00032797B:G02 ES 139 M00032808B:G10 ES 139 M00032811B:D02 ES 139 M00032829B:E06 ES 139 M00032830D:G03 ES 139 M00032831C:G07 ES 139 M00032853D:G12 ES 139 M00032864B:B09 ES 139 M00032871D:E11 ES 139 M00032876C:D06 ES 139 M00032907A:G04 ES 139 M00032909A:B06 ES 139 M00032917D:G09 ES 139 M00032918B:D08 ES 139 M00032918B:E06 ES 139 M00032918C:B10 ES 139 M00032921B:H08 ES 139 M00032933A:C10 ES 139 M00032939B:E07 ES 139 M00032940A:C02 ES 139 M00032942D:C12 ES 139 M00032944B:B02 ES 139 M00032984C:G05 ES 139 M00032990B:A11 ES 139 M00032994A:A08 ES 139 M00032995C:C05 ES 139 M00033007C:E01 ES 139 M00033019B:E10 ES 139 M00033033C:H01 ES 139 M00033034C:A06 ES 139 M00033034C:F02 ES 139 M00033037D:C11 ES 139 M00033074A:C08 ES 139 M00033130B:F06 ES 139 M00033140D:F06 ES 139 M00033173D:C01 ES 139 M00033176B:E12 ES 139 M00033186C:D11 ES 139 M00033189D:F08 ES 139 M00033202D:G06 ES 139 M00033204B:A07 ES 139 M00033205A:F03 ES 139 M00033217B:H07 ES 139 M00033218A:C04 ES 139 M00033223B:H07 ES 139 M00033226A:A11 ES 139 M00033231D:B09 ES 139 M00033231D:G10 ES 139 M00033243B:A05 ES 139 M00033246C:E08 ES 139 M00033248A:B02 ES 139 M00033261C:D12 ES 139 M00033262D:A11 ES 139 M00033263B:G04 ES 139 M00033276B:G08 ES 139 M00033185C:D01 ES 139 M00033288B:D12 ES 140 M00033300D:H12 ES 140 M00033306D:G08 ES 140 M00033306D:H09 ES 140 M00033308B:G05 ES 140 M00033343C:H08 ES 140 M00033345D:A09 ES 140 M00033346C:A05 ES 140 M00033347C:F02 ES 140 M00033349D:F05 ES 140 M00033358A:H12 ES 140 M00033362C:C05 ES 140 M00033375A:G04 ES 140 M00033376A:C12 ES 140 M00033377D:A05 ES 140 M00033410B:C09 ES 140 M00033424B:A04 ES 140 M00033424D:H12 ES 140 M00033425A:C10 ES 140 M00033427D:F01 ES 140 M00033432B:H10 ES 140 M00033437C:A07 ES 140 M00033437C:C03 ES 140 M00033442A:D06 ES 140 M00033446C:G08 ES 140 M00033446D:B02 ES 140 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M00022282B:C09 ES 163 M00022305A:B04 ES 163 M00022363C:D05 ES 163 M00022367D:G11 ES 163 M00022368A:B11 ES 163 M00022372D:H12 ES 163 M00022374C:E11 ES 163 M00022376D:D05 ES 163 M00022383C:A12 ES 163 M00022386D:F10 ES 163 M00022392B:F01 ES 163 M00022403C:E12 ES 164 M00022415C:D12 ES 164 M00022416D:D01 ES 164 M00022421A:F12 ES 164 M00022425A:C09 ES 164 M00022430C:C06 ES 164 M00022435B:G12 ES 164 M00022436C:F11 ES 164 M00022438C:H09 ES 164 M00022442B:G03 ES 164 M00022446C:H06 ES 164 M00022449D:F08 ES 164 M00022452B:E06 ES 164 M00022454C:B08 ES 164 M00022457A:G05 ES 164 M00022467D:B03 ES 164 M00022470D:B02 ES 164 M00022472D:B01 ES 164 M00022474B:C08 ES 164 M00022475D:C07 ES 164 M00022481B:A04 ES 164 M00022485B:E07 ES 164 M00022487B:A08 ES 164 M00022487C:C02 ES 164 M00022491A:A08 ES 164 M00022491D:A10 ES 164 M00022494B:D06 ES 164 M00022494D:A05 ES 164 M00022499D:D08 ES 164 M00022507C:C08 ES 164 M00022509A:H02 ES 164 M00022509B:D11 ES 164 M00022512B:A09 ES 164 M00022516B:C05 ES 164 M00022525B:D09 ES 164 M00022530B:C04 ES 164 M00022537B:C06 ES 164 M00022546B:E05 ES 164 M00022559D:G10 ES 164 M00022563B:C08 ES 164 M00022590B:E05 ES 164 M00022600D:B05 ES 164 M00022601B:G06 ES 164 M00022618B:D09 ES 164 M00022618C:E04 ES 164 M00022627B:H03 ES 164 M00022634A:C07 ES 164 M00022634B:H09 ES 164 M00022638A:D03 ES 164 M00022642A:G08 ES 164 M00022648A:D08 ES 164 M00022656D:D07 ES 164 M00022662C:H04 ES 164 M00022662D:H03 ES 164 M00022672C:H04 ES 164 M00022674C:H08 ES 164 M00022677C:C01 ES 164 M00022678B:C08 ES 164 M00022681D:E10 ES 164 M00022682D:A10 ES 164 M00022684A:E06 ES 164 M00022690A:A07 ES 164 M00022694A:F05 ES 164 M00022696B:C11 ES 164 M00039921C:H11 ES 164 M00039929B:E06 ES 164 M00039929D:H10 ES 164 M00039932B:A07 ES 164 M00039976C:F11 ES 164 M00039977B:D12 ES 164 M00039981D:B01 ES 164 M00040003A:G10 ES 164 M00040016C:E07 ES 164 M00040023B:B10 ES 164 M00040025A:B04 ES 164 M00040034A:E06 ES 164 M00040034B:G02 ES 164 M00040041A:G08 ES 164 M00040041D:F01 ES 164 M00040045B:H07 ES 164 M00040061C:C08 ES 164 M00040075B:A05 ES 164 M00040078A:C07 ES 164 M00040079B:F06 ES 164 M00040079D:D09 ES 164 M00040081C:E02 ES 164 M00040094B:C08 ES 164 M00040118D:C05 ES 164 M00040123C:A10 ES 164 M00040127C:D02 ES 164 M00022698C:D10 ES 164 M00022702D:E02 ES 164 M00022703D:B11 ES 164 M00022706D:G08 ES 164 M00022727A:G01 ES 164 M00022738D:G08 ES 164 M00022740C:H11 ES 165 M00022797D:A06 ES 165 M00022801D:D09 ES 165 M00022805B:A10 ES 165 M00022812A:G01 ES 165 M00022820A:F07 ES 165 M00022835C:A09 ES 165 M00022854C:G07 ES 165 M00022856D:A07 ES 165 M00022857B:A09 ES 165 M00022897B:F06 ES 165 M00022901A:C05 ES 165 M00022904C:D04 ES 165 M00022924B:A05 ES 165 M00022924C:F04 ES 165 M00022945A:H09 ES 165 M00022945B:F11 ES 165 M00022947B:D02 ES 165 M00022952A:B02 ES 165 M00022953B:D06 ES 165 M00022964A:B03 ES 165 M00022972C:E05 ES 165 M00022992A:H06 ES 165 M00022992B:G12 ES 165 M00022995C:G07 ES 165 M00023004C:A01 ES 165 M00023007D:D03 ES 165 M00023020C:H03 ES 165 M00023097D:B08 ES 165 M00039184D:H09 ES 165 M00039364D:E05 ES 165 M00039377B:E05 ES 165 M00039377B:H09 ES 165 M00039483A:D10 ES 165 M00039526A:A08 ES 165 M00039537A:F08 ES 165 M00039564D:D04 ES 165 M00039594C:B06 ES 165 M00039598A:E04 ES 165 M00039630D:B07 ES 165 M00039642A:A08 ES 165 M00039642C:F08 ES 165 M00039646A:E06 ES 165 M00039647A:A02 ES 165 M00039647B:A02 ES 165 M00039739B:H12 ES 165 M00040132A:H09 ES 165 M00040162A:E02 ES 165 M00040169A:G06 ES 165 M00040173D:A04 ES 165 M00040174D:G06 ES 165 M00040198A:F12 ES 165 M00040224C:F06 ES 165 M00040247D:D02 ES 165 M00040252C:G05 ES 165 M00040267D:A12 ES 165 M00040287A:C11 ES 165 M00040287C:F10 ES 165 M00040289D:C06 ES 165 M00039747B:B06 ES 165 M00039748C:G09 ES 165 M00040201A:H01 ES 165 M00040219B:B07 ES 165 M00040291A:G10 ES 165 M00040298B:B09 ES 165 M00040314B:D07 ES 165 M00040326B:G09 ES 165 M00040329A:H05 ES 165 M00040338A:B10 ES 165 M00040344C:D05 ES 165 M00040349D:D07 ES 165 M00040351A:C08 ES 165 M00040351D:G07 ES 165 M00040366B:H10 ES 165 M00040367A:C08 ES 165 M00040381A:B06 ES 165 M00040384B:E04 ES 165 M00040391A:G05 ES 165 M00042525B:H01 ES 165 M00042528C:H01 ES 165 M00042554A:D01 ES 165 M00042557D:B06 ES 165 M00042560C:G06 ES 165 M00042579A:D09 ES 165 M00042719A:G08 ES 165 M00042722C:C09 ES 165 M00042724A:G06 ES 165 M00042732B:H06 ES 165 M00042734A:F05 ES 165 M00042742B:E04 ES 165 M00042743D:G10 ES 165 M00042891C:G08 ES 165 M00042894C:A11 ES 165 M00042908A:F09 ES 165 M00042915B:G11 ES 165 M00054793B:A06 ES 165 M00054911D:E06 ES 166 M00055430A:A01 ES 166 M00055433D:G03 ES 166 M00055448B:E05 ES 166 M00055454A:D02 ES 166 M00055456C:H06 ES 166 M00055466A:F06 ES 166 M00055468A:A08 ES 166 M00055527B:E01 ES 166 M00055639A:E06 ES 166 M00055653C:B07 ES 166 M00055676A:G02 ES 166 M00055724B:E04 ES 166 M00055724D:C07 ES 166 M00055725D:D09 ES 166 M00055735A:H08 ES 166 M00055745B:A08 ES 166 M00055757A:B01 ES 166 M00055794A:E10 ES 166 M00055805A:H02 ES 166 M00055809A:B09 ES 166 M00055810C:D03 ES 166 M00055818B:D01 ES 166 M00055873D:C02 ES 166 M00055880B:H10 ES 166 M00055919B:C10 ES 166 M00055925D:B07 ES 166 M00055961C:B10 ES 166 M00055975B:F09 ES 166 M00055980C:B04 ES 166 M00056004B:C05 ES 166 M00056024B:F09 ES 166 M00056035D:A08 ES 166 M00056057C:F06 ES 166 M00056105A:D06 ES 166 M00056133A:E11 ES 166 M00056215D:F02 ES 166 M00056217D:E10 ES 166 M00056220D:G02 ES 166 M00056230D:E07 ES 166 M00056244A:B06 ES 166 M00056244C:H05 ES 166 M00056304A:H05 ES 166 M00056320B:A03 ES 166 M00056342A:C03 ES 166 M00056345D:A04 ES 166 M00056436C:F01 ES 166 M00056458C:E01 ES 166 M00042350A:A05 ES 166 M00042433A:E11 ES 166 M00042462B:C02 ES 166 M00042512D:D10 ES 166 M00042766C:D05 ES 166 M00042788A:F04 ES 166 M00042794A:F01 ES 166 M00042796A:A10 ES 166 M00042801C:D01 ES 166 M00042822A:H04 ES 166 M00042857C:E01 ES 166 M00042858C:G11 ES 166 M00042860B:C07 ES 166 M00042863D:F09 ES 166 M00042878D:F05 ES 166 M00042878D:G06 ES 166 M00042352B:A04 ES 166 M00042352D:B03 ES 166 M00042449B:F05 ES 166 M00042457C:B06 ES 166 M00042516B:D01 ES 166 M00042520B:H04 ES 166 M00043299A:B10 ES 166 M00043306D:C01 ES 166 M00043313D:E09 ES 166 M00043328C:E04 ES 166 M00043336D:B03 ES 166 M00043339C:F11 ES 166 M00043355A:D07 ES 166 M00043358C:A02 ES 166 M00043402B:G07 ES 166 M00054499A:C08 ES 166 M00054528B:E05 ES 166 M00054536B:B01 ES 166 M00054538D:C12 ES 166 M00054542B:A10 ES 166 M00054548C:H06 ES 166 M00054569A:B07 ES 166 M00054579A:C02 ES 166 M00054599D:B03 ES 166 M00054623C:F05 ES 166 M00054643D:F07 ES 166 M00054675D:G03 ES 166 M00054682B:H02 ES 166 M00054683D:G11 ES 166 M00054686A:A09 ES 166 M00054686A:F10 ES 166 M00054693A:E11 ES 166 M00054708C:B06 ES 167 M00054714B:G10 ES 167 M00054725C:D09 ES 167 M00054744C:F12 ES 167 M00054781B:H04 ES 167 M00054781D:A11 ES 167 M00054786C:D08 ES 167 M00054807D:C11 ES 167 M00054817D:A11 ES 167 M00054818B:F10 ES 167 M00054843A:C01 ES 167 M00054856C:D03 ES 167 M00054866B:C08 ES 167 M00054890C:D05 ES 167 M00054908C:A01 ES 167 M00054931D:E10 ES 167 M00054973B:E12 ES 167 M00054978C:F01 ES 167 M00055001C:G10 ES 167 M00055002B:E08 ES 167 M00055004C:H05 ES 167 M00055023A:E11 ES 167 M00055043B:H08 ES 167 M00055055C:F01 ES 167 M00055081A:A05 ES 167 M00055093B:A03 ES 167 M00055108B:A02 ES 167 M00055117A:E02 ES 167 M00055166C:D10 ES 167 M00055221C:H11 ES 167 M00055232A:E08 ES 167 M00055239D:F11 ES 167 M00055240A:A08 ES 167 M00055244B:F07 ES 167 M00055254A:H03 ES 167 M00055337B:C04 ES 167 M00055375C:F12 ES 167 M00055387C:C12 ES 167 M00055391B:C07 ES 167 M00055395D:D11 ES 167 M00055402A:H01 ES 167 M00055420A:E06 ES 167 M00055423A:B08 ES 167 M00055423C:G12 ES 167 M00055423C:H10 ES 167 M00055424B:H06 ES 167 M00055424D:G05 ES 167 M00055425C:A04 ES 167 M00055473C:F02 ES 167 M00055477D:B01 ES 167 M00042585A:H11 ES 167 M00042585D:D03 ES 167 M00042585D:E10 ES 167 M00042586A:B01 ES 167 M00042588C:E02 ES 167 M00042621C:C04 ES 167 M00042951D:G12 ES 167 M00042960B:C06 ES 167 M00042967D:C01 ES 167 M00042970C:B01 ES 167 M00042972C:F04 ES 167 M00042976D:C01 ES 167 M00042982D:A10 ES 167 M00042986D:E03 ES 167 M00042996B:H08 ES 167 M00043013B:E03 ES 167 M00043015D:D05 ES 167 M00043016B:F09 ES 167 M00043017C:D08 ES 167 M00043063C:H05 ES 167 M00043070A:C03 ES 167 M00043113C:G09 ES 167 M00042617B:E01 ES 167 M00043074C:D07 ES 167 M00043076D:A02 ES 167 M00043077B:F11 ES 167 M00043077C:D12 ES 167 M00043077C:G10 ES 167 M00043099A:H04 ES 167 M00043101D:G11 ES 167 M00043134A:F05 ES 167 M00043152C:B10 ES 167 M00043213A:D05 ES 167 M00043219C:C02 ES 167 M00043221D:C12 ES 167 M00043222C:B06 ES 167 M00043455B:C08 ES 167 M00043465C:H11 ES 167 M00043470A:C10 ES 167 M00043485C:C03 ES 167 M00043490C:F02 ES 167 M00043495C:H05 ES 167 M00043528A:E11 ES 167 M00043529A:B08 ES 167 M00043640A:B01 ES 167

Example 68 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from mRNA isolated from the cell lines indicated in Table 109. The specific library from which any polynucleotide was isolated is indicated in Table 106, with the number of the entry under the “LIBRARY” column correlating to the library number in Table 109. Polynucleotides expressed by the selected cell lines were isolated and analyzed; the sequences of these polynucleotides were about 275-300 nucleotides in length.

The sequences of the isolated polynucleotides were fist masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. The remaining sequences were then used in a BLASTN vs. GenBank search; sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the GenBank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded. Second, a BLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p value less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 2396 sequences listed as SEQ ID NOS:13271-15666 in the accompanying Sequence Listing and summarized in Table 106. Each identified polynucleotide represents sequence from at least a partial mRNA transcript.

Table 106 provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the cluster to which the sequence is assigned; 3) the sequence name used as an internal identifier of the sequence; 4) the orientation of the insert in the clone (F=forward; R=reverse); 5) the name assigned to the clone from which the sequence was isolated; and 6) the library from which the sequence was originally isolated. Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene.

Example 69 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS:13271-15666 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in either the GenBank (nucleotide sequences) or Non-Redundant Protein (amino acid sequences) databases. Query and individual sequences were aligned using the BLAST 2.0 programs (National Center for Biotechnology Information, Bethesda, Md.; see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above in Example 68.

Tables 107A and 107B (inserted before the claims) provide the alignment summaries having a p value of 1×10⁻² or less indicating substantial homology between the sequences of the present invention and those of the indicated public databases. Table 107A provides the SEQ ID NO of the query sequence, the accession number of the GenBank database entry of the homologous sequence, and the p value of the alignment. Table 107B provides the SEQ ID NO of the query sequence, the accession number of the Non-Redundant Protein database entry of the homologous sequence, and the p value of the alignment. The alignments provided in Tables 107A and 107B are the best available alignment to a DNA or amino acid sequence at a time just prior to filing of the present specification. The activity of the polypeptide encoded by the SEQ ID NOS listed in Tables 107A and 107B can be extrapolated to be substantially the same or substantially similar to the activity of the reported nearest neighbor or closely related sequence. The accession number of the nearest neighbor is reported, providing a publicly available reference to the activities and functions exhibited by the nearest neighbor. The public information regarding the activities and functions of each of the nearest neighbor sequences is incorporated by reference in this application. Also incorporated by reference is all publicly available information regarding the sequence, as well as the putative and actual activities and functions of the nearest neighbor sequences listed in Table 107B and their related sequences. The search program and database used for the alignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of the corresponding polynucleotide. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of the corresponding polynucleotides.

Example 70 Members of Protein Families

SEQ ID NOS: 13271-15666 were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein family (and thus represent members of these protein families) and/or comprising a known functional domain. Table provides the SEQ ID NO: of the query sequence, the profile name, and a brief description of the profile hit.

TABLE 108 SEQ ID Profilename Description 13680 ATPases ATPases Associated with Various Cellular Activities 13807 ATPases ATPases Associated with Various Cellular Activities 13809 ATPases ATPases Associated with Various Cellular Activities 13810 ATPases ATPases Associated with Various Cellular Activities 13932 rrm RNA recognition motif. (aka RRM, RBD or RNP domain) 13953 rrm RNA recognition motif. (aka RRM, RBD, or RNP domain) 13977 dualspecphosphatase Dual specificity phosphatase, catalytic domain 13978 rrm RNA recognition motif. (aka RRM, RBD, or RNP domain) 13989 EFhand EF-hand 14008 ATPases ATPases Associated with Various Cellular Activities 14049 Zincfing_C2H2 Zinc finger, C2H2 type 14051 rrm RNA recognition motif. (aka RRM, RBD, or RNP domain) 14053 rrm RNA recognition motif. (aka RRM, RBD, or RNP domain) 14380 WD_domain WD domain, G-beta repeats 14685 Dead_box_helic DEAD and DEAH box helicases 14803 C2 C2 domain (prot. kinase C like) 14903 dualspecphosphatase Dual specificity phosphatase, catalytic domain 14907 Dead_box_helic DEAD and DEAH box helicases 14908 Dead_box_helic DEAD and DEAH box helicases 15014 WD_domain WD domain, G-beta repeats 15029 BZIP Basic region plus leucine zipper transcription factors 15263 WD_domain WD domain, G-beta repeats 15353 WD_domain WD domain, G-beta repeats 15479 ATPases ATPases Associated with Various Cellular Activities 15498 ras Ras family 15557 ras Ras family 15570 neur_chan Neurotransmitter-gated ion-channel 15572 tor_domain2 kinase domain of tors (Christoph Reinhard) 15576 homeobox Homeobox Domain 15588 Metallothion Metallothioneins 15597 asp Eukaryotic aspartyl proteases

Some polynucleotides exhibited multiple profile hits where the query sequence contains overlapping profile regions, and/or where the sequence contains two different functional domains. Each of the profile hits of Table 108 are described in more detail below. The acronyms for the profiles (provided in parentheses) are those used to identify the profile in the Pfam and Prosite databases. The Pfam database can be accessed through web sites supported by the Washington University, St. Louis (Mo.), The Sanger Centre (United Kingdom); and The Karolinska Institute Center for Genomics Research. The Prosite database is publicaly available through the ExPASy Molecular Biology Server. The public information available on the Pfam and Prosite databases regarding the various profiles, including but not limited to the activities, function, and consensus sequences of various proteins families and protein domains, is incorporated herein by reference.

Eukaryotic Aspartyl Proteases (asp; Pfam Accession No. PF00026). One SEQ ID NO corresponds to a gene encoding a novel eukaryotic aspartyl protease. Aspartyl proteases, known as acid proteases, (EC 3.4.23.-) are a widely distributed family of proteolytic enzymes (Foltmann B., Essays Biochem. (1981) 17:52; Davies D. R., Annu. Rev. Biophys. Chem. (1990) 19:189; Rao J. K. M., et al., Biochemistry (1991) 30:4663) known to exist in vertebrates, fungi, plants, retroviruses and some plant viruses. Aspartate proteases of eukaryotes are monomeric enzymes which consist of two domains.

ATPases Associated with Various Cellular Activities (ATPases; Pfam Accession No. PF0004). Some SEQ ID NOS correspond to a sequence that encodes a member of a family of ATPases Associated with diverse cellular Activities (AAA). The AAA protein family is composed of a large number of ATPases that share a conserved region of about 220 amino acids containing an ATP-binding site (Froehlich et al., J. Cell Biol. (1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209-224; Confalonieri et al., BioEssays (1995) 17:639; see also the AAA Server Homepage). The AAA domain, which can be present in one or two copies, acts as an ATP-dependent protein clamp (Confalonieri et al. (1995) BioEssays 17:639) and contains a highly conserved region located in the central part of the domain.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP; Pfam Accession No. PF00170). One SEQ ID NO represents a polynucleotide encoding a novel member of the family of basic region plus leucine zipper transcription factors. The bZIP superfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcription factors encompasses proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper required for dimerization.

C2 domain (C2; Pfam Accession No. PF00168). ONe SEQ ID NO corresponds to a sequence encoding a C2 domain, which is involved in calcium-dependent phospholipid binding (Davletov J. Biol. Chem. (1993) 268:26386-26390) or, in proteins that do not bind calcium, the domain may facilitate binding to inositol-1,3,4,5-tetraphosphate (Fukuda et al. J. Biol. Chem. (1994) 269:29206-29211; Sutton et al. Cell (1995) 80:929-938).

DEAD and DEAH box families ATP-dependent helicases (Dead_box_helic; Pfam Accession No. PF00270). Some SEQ ID NOS represent polynucleotides encoding a novel member of the DEAD and DEAH box families (Schmid et al., Mol. Microbiol. (1992) 6:283; Linder et al., Nature (1989) 337:121; Wassarman, et al., Nature (1991) 349:463). All members of these families are involved in ATP-dependent, nucleic-acid unwinding. All DEAD box family members share a number of conserved sequence motifs, some of which are specific to the DEAD family, with others shared by other ATP-binding proteins or by proteins belonging to the helicases ‘superfamily’ (Hodgman Nature (1988) 333:22 and Nature (1988) 333:578 (Errata)). One of these motifs, called the ‘D-E-A-D-box’, represents a special version of the B motif of ATP-binding proteins. Proteins that have His instead of the second Asp and are ‘D-E-A-H-box’ proteins (Wassarman et al., Nature (1991) 349:463; Harosh, et al., Nucleic Acids Res. (1991) 19:6331; Koonin, et al., J. Gen. Virol. (1992) 73:989).

Dual specificity phosphatase (DSPc; Pfam Accession No. PF00782). Some SEQ ID NOS correspond to sequences that encode members of a family of dual specificity phosphatases (DSPs). DSPs are Ser/Thr and Tyr protein phosphatases that comprise a tertiary fold highly similar to that of tyrosine-specific phosphatases, except for a “recognition” region connecting helix alpha1 to strand beta1. This tertiary fold may determine differences in substrate specific between VH-1 related dual specificity phosphatase (VHR), the protein tyrosine phosphatases (PTPs), and other DSPs. Phosphatases are important in the control of cell growth, proliferation, differentiation and transformation.

EF Hand (Efhand; Pfam Accession No. PF00036). One SEQ ID NO corresponds to a polynucleotide encoding a member of the EF-hand protein family, a calcium binding domain shared by many calcium-binding proteins belonging to the same evolutionary family (Kawasaki et al., Protein. Prof. (1995) 2:305-490). The domain is a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain, with a calcium ion coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, −Y, −X and −Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).

Homeobox domain (homeobox; Pfam Accession No. PF00046). One SEQ ID NO represents a polynucleotide encoding a protein having a homeobox domain. The ‘homeobox’ is a protein domain of 60 amino acids (Gehring In: Guidebook to the Homebox Genes, Duboule D., Ed., pp 1-10, Oxford University Press, Oxford, (1994); Buerglin In: Guidebook to the Homebox Genes, pp 25-72, Oxford University Press, Oxford, (1994); Gehring Trends Biochem. Sci. (1992) 17:277-280; Gehring et al Annu. Rev. Genet. (1986) 20:147-173; Schofield Trends Neurosci. (1987) 10:3-6) first identified in number of Drosophila homeotic and segmentation proteins. It is extremely well conserved in many other animals, including vertebrates. This domain binds DNA through a helix-turn-helix type of structure. Several proteins that contain a homeobox domain play an important role in development. Most of these proteins are sequence-specific DNA-binding transcription factors. The homeobox domain is also very similar to a region of the yeast mating type proteins. These are sequence-specific DNA-binding proteins that act as master switches in yeast differentiation by controlling gene expression in a cell type-specific fashion.

A schematic representation of the homeobox domain is shown below. The helix-turn-helix region is shown by the symbols ‘H’ (for helix), and ‘t’ (for turn).

The pattern detects homeobox sequences 24 residues long and spans positions 34 to 57 of the homeobox domain.

Metallothioneins (metalthio; Pfam Accession No. PF00131). One SEQ ID NO corresponds to a polynucleotide encoding a member of the metallothionein (MT) protein family (Hamer Annu. Rev. Biochem. (1986) 55:913-951; and Kagi et al. Biochemistry (1988) 27:8509-8515), small proteins which bind heavy metals such as zinc, copper, cadmium, nickel, etc., through clusters of thiolate bonds. MT's occur throughout the animal kingdom and are also found in higher plants, fungi and some prokaryotes. On the basis of structural relationships MT's have been subdivided into three classes. Class I includes mammalian MT's as well as MT's from crustacean and molluscs, but with clearly related primary structure. Class II groups together MT's from various species such as sea urchins, fungi, insects and cyanobacteria which display none or only very distant correspondence to class I MT's. Class III MT's are atypical polypeptides containing gamma-glutamylcysteinyl units.

Neurotransmitter-Gated Ion-Channel (neur_chan; Pfam Accession No. PF00065). One SEQ ID NO corresponds to a sequence encoding a neurotransmitter-gated ion channel. Neurotransmitter-gated ion-channels, which provide the molecular basis for rapid signal transmission at chemical synapses, are post-synaptic oligomeric transmembrane complexes that transiently form a ionic channel upon the binding of a specific neurotransmitter. Five types of neurotransmitter-gated receptors are known: 1) nicotinic acetylcholine receptor (AchR); 2) glycine receptor; 3) gamma-aminobutyric-acid (GABA) receptor; 4) serotonin 5HT3 receptor; and 5) glutamate receptor. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related, and are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions that form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence.

Ras family proteins (ras; Pfam Accession No. PF00071). Some SEQ ID NOS represent polynucleotides encoding the ras family of small GTP/GDP-binding proteins (Valencia et al., 1991, Biochemistry 30:4637-4648). Ras family members generally require a specific guanine nucleotide exchange factor (GEF) and a specific GTPase activating protein (GAP) as stimulators of overall GTPase activity. Among ras-related proteins, the highest degree of sequence conservation is found in four regions that are directly involved in guanine nucleotide binding. The first two constitute most of the phosphate and Mg2+ binding site (PM site) and are located in the first half of the G-domain. The other two regions are involved in guanosine binding and are located in the C-terminal half of the molecule. Motifs and conserved structural features of the ras-related proteins are described in Valencia et al., 1991, Biochemistry 30:4637-4648.

RNA Recognition Motif (rrm; Pfam Accession No. PF00076). Some SEQ ID NOS correspond to sequence encoding an RNA recognition motif, also known as an RRM, RBD, or RNP domain. This domain, which is about 90 amino acids long, is contained in eukaryotic proteins that bind single-stranded RNA (Bandziulis et al. Genes Dev. (1989) 3:431-437; Dreyfuss et al. Trends Biochem. Sci. (1988) 13:86-91). Two regions within the RNA-binding domain are highly conserved: the first is a hydrophobic segment of six residues (which is called the RNP-2 motif), the second is an octapeptide motif (which is called RNP-1 or RNP-CS).

Kinase Domain of Tors (tor_domain2). One SEQ ID NO corresponds to a member of the TOR lipid kinase protein family. This family is composed of large proteins with a lipid and protein kinase domain and characterized through their sensitivity to rapamycin (an antifungal compound). TOR proteins are involved in signal transduction downstream of PI3 kinase and many other signals. TOR (also called FRAP, RAFT) plays a role in regulating protein synthesis and cell growth, and in yeast controls translation initiation and early G1 progression. See, e.g., Barbet et al. Mol Biol Cell. (1996) 7(1):25-42; Helliwell et al. Genetics (1998) 148:99-112.

WD Domain, G-Beta Repeats (WD_domain: Pfam Accession No. PF00400). Some SEQ ID NOS represent novel members of the WD domain/G-beta repeat family. Beta-transducin (G-beta) is one of the three subunits (alpha, beta, and gamma) of the guanine nucleotide-binding proteins (G proteins) which act as intermediaries in the transduction of signals generated by transmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds to and hydrolyzes GTP; the functions of the beta and gamma subunits are less clear but they seem to be required for the replacement of GDP by GTP as well as for membrane anchoring and receptor recognition. In higher eukaryotes, G-beta exists as a small multigene family of highly conserved proteins of about 340 amino acid residues. Structurally, G-beta consists of eight tandem repeats of about 40 residues, each containing a central Trp-Asp motif (this type of repeat is sometimes called a WD-40 repeat).

Zinc Finger, C2H2 Type (Zincfing_C2H2; Pfam Accession No. PF00096). One SEQ ID NO corresponds to a polynucleotide encoding a member of the C2H2 type zinc finger protein family, which contain zinc finger domains that facilitate nucleic acid binding (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99).

In addition to the conserved zinc ligand residues, a number of other positions are also important for the structural integrity of the C2H2 zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved position, which is generally an aromatic or aliphatic residue, is located four residues after the second cysteine.

Example 71 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 109 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, and the approximate number of clones in the library.

TABLE 109 Description of cDNA Libraries Number of Library Clones in (Lib#) Description Library 1 Human Colon Cell Line Km12 L4: High Metastatic 308731 Potential (derived from Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic Potential 284771 3 Human Breast Cancer Cell Line MDA-MB-231: High 326937 Metastatic Potential; micro-mets in lung 4 Human Breast Cancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung Cancer Cell Line MV-522: High Metastatic 223620 Potential 9 Human Lung Cancer Cell Line UCP-3: Low Metastatic 312503 Potential 12 Human microvascular endothelial cells (HMVEC) - 41938 UNTREATED (PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells (HMVEC) - bFGF 42100 TREATED (PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells (HMVEC) - VEGF 42825 TREATED (PCR (OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTED PCR 282722 (OligodT) cDNA library) 16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR 298831 (OligodT) cDNA library) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467 (MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED PCR 36216 (OligodT) cDNA library) 19 Colon Tumor - UC#3 Patient (MICRODISSECTED PCR 41388 (OligodT) cDNA library) 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 (MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived from normal prostate epithelium 164801 22 WOca Cells derived from Gleason Grade 4 prostate cancer 162088 epithelium 23 Normal Lung Epithelium of Patient #1006 306198 (MICRODISSECTED PCR (OligodT) cDNA library) 24 Primary tumor, Large Cell Carcinoma of Patient #1006 309349 (MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4 cell line (Morikawa, et al., Cancer Research (1988) 48:6863) is derived from the KM12C cell line (Morikawa et al. Cancer Res. (1988) 48:1943-1948). The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KM12L4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246). The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MDA-MB-231 and MCF-7 cell lines are well-recognized in the art as a models for the study of human breast cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870; Gastpar et al., J Med Chem (1998) 41:4965; Ranson et al., Br J Cancer (1998) 77:1586; and Kuang et al., Nucleic Acids Res (1998) 26:1116).

The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human lung cancer (see, e.g., Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cell lines were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974).

Example 72 Differential Expression of Genes Corresponding to Polynucleotides of the Invention

A number of polynucleotide sequences have been identified that are differentially expressed between, for example, cells derived from high metastatic potential cancer tissue and low metastatic cancer cells, and between cells derived from metastatic cancer tissue and normal tissue. Evaluation of the levels of expression of the genes corresponding to these sequences can be valuable in diagnosis, prognosis, and/or treatment (e.g., to facilitate rationale design of therapy, monitoring during and after therapy, etc.). Moreover, the genes corresponding to differentially expressed sequences described herein can be therapeutic targets due to their involvement in regulation (e.g., inhibition or promotion) of development of, for example, the metastatic phenotype. For example, sequences that correspond to genes that are increased in expression in high metastatic potential cells relative to normal or non-metastatic tumor cells may encode genes or regulatory sequences involved in processes such as angiogenesis, differentiation, cell replication, and metastasis.

Detection of the relative expression levels of differentially expressed polynucleotides described herein can provide valuable information to guide the clinician in the choice of therapy. For example, a patient sample exhibiting an expression level of one or more of these polynucleotides that corresponds to a gene that is increased in expression in metastatic or high metastatic potential cells may warrant more aggressive treatment for the patient. In contrast, detection of expression levels of a polynucleotide sequence that corresponds to expression levels associated with that of low metastatic potential cells may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of the polynucleotides described herein can thus be used as, for example, diagnostic markers, prognostic markers, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers. The following examples provide relative expression levels of polynucleotides from specified cell lines and patient tissue samples.

The differential expression data for polynucleotides of the invention that have been identified as being differentially expressed across various combinations of the libraries described above is summarized in Table 110 (inserted prior to the claims). Table 110 provides: 1) the Sequence Identification Number (“SEQ”) assigned to the polynucleotide; 2) the cluster (“CLST”) to which the polynucleotide has been assigned as described above; 3) the library comparisons that resulted in identification of the polynucleotide as being differentially expressed (“Library Pair A,B”), with shorthand names of the compared libraries provided in parentheses following the library numbers; 4) the number of clones corresponding to the polynucleotide in the first library listed (“A”); 5) the number of clones corresponding to the polynucleotide in the second library listed (“B”); 6) the “A/B” where the comparison resulted in a finding that the number of clones in library A is greater than the number of clones in library B; and 7) the “B/A” where the comparison resulted in a finding that the number of clones in library B is greater than the number of clones in library A.

Example 73 Source of Biological Materials for Microarray-Based Experiments

The biological materials used in the experiments described in the subsequent examples relating to microarry data are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001). Table 114 provides information about each patient from which the samples were isolated, including: the Patient ID and Path ReportID, numbers assigned to the patient and the pathology reports for identification purposes; the anatomical location of the tumor (AnatomicalLoc); The Primary Tumor Size; the Primary Tumor Grade; the Histopathologic Grade; a description of local sites to which the tumor had invaded (Local Invasion); the presence of lymph node metastases (Lymph Node Metastasis); incidence of lymph node metastases (provided as number of lymph nodes positive for metastasis over the number of lymph nodes examined) (Incidence Lymphnode Metastasis); the Regional Lymphnode Grade; the identification or detection of metastases to sites distant to the tumor and their location (Distant Met & Loc); a description of the distant metastases (Description Distant Met); the grade of distant metastasis (Distant Met Grade); and general comments about the patient or the tumor (Comments). Adenoma was not described in any of the patients; adenoma dysplasia (described as hyperplasia by the pathologist) was described in Patient ID No. 695. Extranodal extensions were described in two patients, Patient ID Nos. 784 and 791. Lymphovascular invasion was described in seven patients, Patient ID Nos. 128, 278, 517, 534, 784, 786, and 791. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791.

Polynucleotides on Arrays

Polynucleotides spotted on the arrays were generated by PCR amplification of clones derived from cDNA libraries. The clones used for amplification were either the clones from which the sequences described herein (SEQ ID NOS: 13271-15666) were derived, or are clones having inserts with significant polynucleotide sequence overlap with the sequences described herein (SEQ ID NO: 13271-15666) as determined by BLAST2 homology searching.

Example 74 Microarray Design

Each array used in the examples below had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array. Spotting was accomplished using PCR amplified products from 0.5 kb to 2.0 kb and spotted using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides.

The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about 4 duplicate measurements for each clone, two of one color and two of the other, for each sample.

Example 75 Identification of Differentially Expressed Genes

cDNA probes were prepared from total RNA isolated from the patient cells described in Example 6. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling. Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red).

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Tables 115-119 summarizes the results of the differential expression analysis, where the difference in the expression level in the colon tumor cell relative to the matched normal colon cells is greater than or equal to 2 fold (“>=2×”), 2.5 fold (“>=2.5×”), or 5 fold (“>=5×”) in at least 20% or more of the patients analyzed. Each table provides: the SEQ ID NO; the percentage of patients tested having a colon tumor that exhibited at least 2 fold (“>=2×”), 2.5 fold (“>=2.5×”), or 5 fold (“>=5×”) increase in expression levels of the indicated gene relative to matched normal colon tissue; and the ratio data for each patient sample tested (columns headed by “P#,” indicating the Patient Identification Number, e.g., “P15” indicates the ration data for patient 15).

TABLE 115 % Pts SEQ ID % Pts >=2_5x % Pts NO >=2x T/N T/N >=5x T/N P15 P52 P121 P125 13288 30.3 15.2 3.0 1.855 2.705 1.000 2.280 13292 45.5 39.4 18.2 2.196 1.719 0.604 2.388 13397 27.3 18.2 6.1 1.000 1.620 1.822 1.692 13409 21.2 18.2 15.2 1000.000 0.001 2.345 1.000 13418 27.3 18.2 6.1 1.000 1.620 1.822 1.692 13425 45.5 12.1 3.0 1.870 3.104 1.361 2.388 13516 42.4 9.1 0.0 2.211 2.347 1.000 1.493 13542 48.5 27.3 12.1 1.735 3.110 1.379 2.277 13543 21.2 18.2 18.2 1.000 1.000 0.330 1.349 13549 24.2 12.1 0.0 1.614 2.348 1.498 1.916 13568 21.2 18.2 18.2 1.000 1.000 0.330 1.349 13599 21.2 9.1 6.1 1.000 1.000 2.211 1.182 13623 45.5 12.1 3.0 1.870 3.104 1.361 2.388 13624 48.5 30.3 3.0 1.000 1.592 2.248 2.315 13651 27.3 18.2 6.1 1.000 1.620 1.822 1.692 13659 21.2 9.1 6.1 1.000 1.000 2.211 1.182 13675 21.2 9.1 3.0 1.000 2.366 1.546 1.562 13676 21.2 9.1 3.0 1.000 2.366 1.546 1.562 13682 36.4 18.2 0.0 2.584 1.332 1.952 1.641 13691 51.5 24.2 3.0 2.481 2.253 2.234 1.431 13735 21.2 18.2 15.2 1000.000 0.001 2.345 1.000 13804 21.2 9.1 3.0 1.000 2.366 1.546 1.562 13808 42.4 15.2 0.0 1.489 2.019 3.022 1.121 13835 45.5 12.1 3.0 1.870 3.104 1.361 2.388 13927 45.5 30.3 3.0 1.512 2.748 0.784 2.162 13940 24.2 6.1 0.0 1.190 1.000 0.656 1.456 14009 21.2 12.1 0.0 1.936 1.830 0.831 1.347 14011 48.5 18.2 0.0 2.750 2.458 1.485 1.151 14014 48.5 21.2 0.0 2.069 3.002 1.229 1.631 14025 30.3 18.2 3.0 1.000 1.414 1.236 1.738 14027 21.2 15.2 6.1 1.000 0.839 2.032 2.557 14080 30.3 18.2 3.0 1.000 1.414 1.236 1.738 14081 30.3 18.2 3.0 1.000 1.414 1.236 1.738 14115 30.3 15.2 9.1 1.000 0.271 0.860 1.310 14131 24.2 21.2 15.2 1000.000 1000.000 1.000 1.320 14185 30.3 15.2 3.0 1.855 2.705 1.000 2.280 14224 24.2 21.2 15.2 1000.000 1000.000 1.000 1.320 14225 39.4 21.2 3.0 1.612 2.281 0.785 2.045 14261 39.4 21.2 3.0 1.612 2.281 0.785 2.045 14305 24.2 6.1 0.0 1.190 1.000 0.656 1.456 14319 21.2 12.1 0.0 1.936 1.830 0.831 1.347 14320 39.4 21.2 3.0 1.612 2.281 0.785 2.045 14505 45.5 12.1 3.0 1.870 3.104 1.361 2.388 14562 21.2 3.0 0.0 1.558 2.014 2.250 1.643 14583 24.2 6.1 0.0 1.190 1.000 0.656 1.456 14601 27.3 9.1 3.0 1.327 3.749 1.000 2.045 14604 48.5 30.3 3.0 1.000 1.592 2.248 2.315 14688 30.3 15.2 3.0 1.855 2.705 1.000 2.280 14689 45.5 12.1 3.0 1.870 3.104 1.361 2.388 14690 39.4 18.2 3.0 1.759 1.566 1.000 2.302 14747 39.4 18.2 3.0 1.759 1.566 1.000 2.302 14824 33.3 15.2 0.0 1.829 1.622 1.882 1.957 14849 42.4 9.1 0.0 2.211 2.347 1.000 1.493 14870 45.5 12.1 3.0 1.870 3.104 1.361 2.388 14909 48.5 27.3 12.1 1.735 3.110 1.379 2.277 14927 42.4 24.2 0.0 1.000 1.908 2.267 1.188 14949 33.3 15.2 0.0 1.829 1.622 1.882 1.957 15014 42.4 15.2 3.0 2.059 2.753 1.679 1.587 15117 78.8 63.6 9.1 2.625 4.493 1.642 2.743 15147 45.5 12.1 3.0 1.870 3.104 1.361 2.388 15150 66.7 48.5 6.1 1.000 4.075 1.754 2.436 15159 45.5 12.1 3.0 1.870 3.104 1.361 2.388 15279 30.3 15.2 3.0 1.855 2.705 1.000 2.280 15293 30.3 18.2 0.0 1.285 2.400 0.767 1.270 15299 42.4 9.1 0.0 2.211 2.347 1.000 1.493 15341 24.2 6.1 0.0 1.190 1.000 0.656 1.456 15347 24.2 6.1 0.0 1.190 1.000 0.656 1.456 15373 27.3 21.2 0.0 3.505 0.793 0.809 1.348 15379 24.2 6.1 0.0 1.190 1.000 0.656 1.456 15408 33.3 21.2 9.1 1.000 0.296 3.016 0.794 15413 60.6 48.5 12.1 6.263 1.000 1.832 1.937 15453 63.6 45.5 12.1 1.945 2.010 0.547 3.325 15455 30.3 18.2 3.0 1.000 1.414 1.236 1.738 15460 24.2 6.1 0.0 1.190 1.000 0.656 1.456 15470 45.5 12.1 3.0 1.870 3.104 1.361 2.388 15476 60.6 27.3 3.0 2.256 2.228 1.673 1.937 15490 33.3 24.2 3.0 2.591 0.483 2.580 1.440 15494 48.5 36.4 3.0 1.602 3.209 1.000 2.942 15519 45.5 12.1 3.0 1.870 3.104 1.361 2.388 15525 24.2 3.0 0.0 1.985 2.261 1.000 0.904 15535 54.5 42.4 6.1 1.886 1.000 1.503 3.375 15537 84.8 57.6 18.2 2.529 3.042 2.471 1.669 15551 54.5 36.4 3.0 2.008 0.686 3.104 1.362 15564 30.3 15.2 3.0 1.855 2.705 1.000 2.280 15570 30.3 15.2 3.0 1.855 2.705 1.000 2.280 15577 42.4 9.1 0.0 2.211 2.347 1.000 1.493 15579 42.4 21.2 9.1 2.497 1.837 3.249 1.497 15583 57.6 48.5 9.1 2.603 2.642 1.000 1.939 15584 48.5 27.3 12.1 1.735 3.110 1.379 2.277 15586 42.4 9.1 0.0 2.211 2.347 1.000 1.493 15597 39.4 24.2 3.0 2.006 1.692 1.778 1.662 15618 72.7 45.5 0.0 2.961 3.152 2.712 1.346

TABLE 116 SEQ ID NO P128 P130 P133 P141 P156 P228 P264 P266 13288 0.713 1.800 1.955 0.663 0.466 1.457 2.262 1.236 13292 1.594 6.800 1.340 1.131 1.000 2.647 1.628 1.190 13397 3.761 1.000 1.000 1.587 2.127 1.000 1.000 1.000 13409 1000.000 1.000 1000.000 0.482 2.846 0.767 1.631 1.000 13418 3.761 1.000 1.000 1.587 2.127 1.000 1.000 1.000 13425 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 13516 1.779 1.337 2.865 1.515 1.617 1.301 2.098 1.733 13542 2.044 2.219 4.257 0.744 1.000 1.127 1.588 1.634 13543 1000.000 1000.000 1.000 1.000 0.566 1.554 1.000 1.000 13549 1.202 1.852 2.370 1.000 1.000 1.114 1.399 1.239 13568 1000.000 1000.000 1.000 1.000 0.566 1.554 1.000 1.000 13599 3.234 0.001 1.000 8.480 2.077 1.000 0.001 1.445 13623 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 13624 1.664 1.987 2.307 2.728 1.000 1.239 1.469 2.059 13651 3.761 1.000 1.000 1.587 2.127 1.000 1.000 1.000 13659 3.234 0.001 1.000 8.480 2.077 1.000 0.001 1.445 13675 1.531 1.553 1.854 2.044 1.363 1.786 1.877 1.644 13676 1.531 1.553 1.854 2.044 1.363 1.786 1.877 1.644 13682 1.831 1.503 2.326 1.130 1.773 1.379 2.318 2.019 13691 2.209 1.889 3.114 1.776 1.788 1.879 2.666 2.257 13735 1000.000 1.000 1000.000 0.482 2.846 0.767 1.631 1.000 13804 1.531 1.553 1.854 2.044 1.363 1.786 1.877 1.644 13808 1.559 1.000 1.740 3.133 2.186 1.869 2.023 2.483 13835 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 13927 1.524 1.770 2.846 1.185 1.000 1.460 1.831 2.261 13940 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 14009 0.845 1.286 1.872 1.000 1.000 1.295 1.722 1.785 14011 1.819 1.801 3.227 1.457 2.960 1.388 2.086 2.410 14014 2.515 1.605 2.399 1.803 2.524 1.551 2.284 1.574 14025 1.000 0.754 2.234 3.723 1.000 1.285 1.771 2.246 14027 0.745 1.332 1000.000 1.000 1.000 1.781 1.515 1.747 14080 1.000 0.754 2.234 3.723 1.000 1.285 1.771 2.246 14081 1.000 0.754 2.234 3.723 1.000 1.285 1.771 2.246 14115 2.331 1.641 1000.000 1.252 1.000 0.595 1.950 0.616 14131 2.888 1.000 0.001 1.000 1.694 0.001 1000.000 1.423 14185 0.713 1.800 1.955 0.663 0.466 1.457 2.262 1.236 14224 2.888 1.000 0.001 1.000 1.694 0.001 1000.000 1.423 14225 1.415 2.042 2.733 0.898 1.431 1.000 1.459 2.009 14261 1.415 2.042 2.733 0.898 1.431 1.000 1.459 2.009 14305 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 14319 0.845 1.286 1.872 1.000 1.000 1.295 1.722 1.785 14320 1.415 2.042 2.733 0.898 1.431 1.000 1.459 2.009 14505 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 14562 1.804 1.641 1.876 1.335 0.766 1.245 1.500 1.000 14583 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 14601 1.427 1.669 1.837 1.265 1.000 1.667 1.000 1.374 14604 1.664 1.987 2.307 2.728 1.000 1.239 1.469 2.059 14688 0.713 1.800 1.955 0.663 0.466 1.457 2.262 1.236 14689 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 14690 1.518 1.997 2.298 2.273 1.000 1.234 1.186 1.730 14747 1.518 1.997 2.298 2.273 1.000 1.234 1.186 1.730 14824 2.959 1.821 2.234 1.181 1.827 1.000 2.042 1.970 14849 1.779 1.337 2.865 1.515 1.617 1.301 2.098 1.733 14870 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 14909 2.044 2.219 4.257 0.744 1.000 1.127 1.588 1.634 14927 2.160 1.416 1.000 3.531 2.974 1.798 1.899 2.065 14949 2.959 1.821 2.234 1.181 1.827 1.000 2.042 1.970 15014 1.479 1.669 2.442 1.352 1.367 1.605 2.145 2.098 15117 1.839 2.548 2.954 2.234 1.816 1.352 3.390 2.541 15147 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 15150 2.762 2.081 4.111 2.306 2.391 1.675 2.572 3.031 15159 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 15279 0.713 1.800 1.955 0.663 0.466 1.457 2.262 1.236 15293 1.871 1.869 2.588 1.834 1.718 1.197 1.965 2.023 15299 1.779 1.337 2.865 1.515 1.617 1.301 2.098 1.733 15341 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 15347 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 15373 2.297 0.855 1.659 1.607 0.252 1.602 2.866 1.292 15379 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 15408 2.074 1.438 1.552 2.403 0.647 0.605 0.469 0.528 15413 2.828 2.795 2.732 2.548 0.073 1.201 1.722 1.181 15453 1.714 3.061 4.635 1.688 1.230 1.241 1.237 1.852 15455 1.000 0.754 2.234 3.723 1.000 1.285 1.771 2.246 15460 1.182 1.636 1.418 1.298 1.000 1.000 1.127 0.774 15470 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 15476 2.229 2.131 2.194 2.235 2.121 1.388 3.468 2.115 15490 2.650 0.815 1.629 1.586 0.155 1.408 2.830 1.636 15494 1.385 2.044 2.510 0.628 1.763 1.000 1.000 1.687 15519 2.062 1.781 2.302 1.000 1.000 1.306 2.099 1.357 15525 1.454 1.000 1.567 2.350 1.729 2.071 1.439 1.540 15535 2.843 2.931 1.690 1.678 0.724 2.656 2.035 3.526 15537 2.490 1.937 3.729 2.105 2.224 2.547 2.605 4.402 15551 3.412 2.374 1.404 4.761 3.241 2.253 1.384 1.912 15564 0.713 1.800 1.955 0.663 0.466 1.457 2.262 1.236 15570 0.713 1.800 1.955 0.663 0.466 1.457 2.262 1.236 15577 1.779 1.337 2.865 1.515 1.617 1.301 2.098 1.733 15579 1.496 1.483 2.427 1.764 1.000 1.231 1.413 1.000 15583 1.452 1.915 2.252 1.342 2.516 1.278 2.179 4.223 15584 2.044 2.219 4.257 0.744 1.000 1.127 1.588 1.634 15586 1.779 1.337 2.865 1.515 1.617 1.301 2.098 1.733 15597 1.778 1.200 2.169 1.462 1.570 1.784 1.937 2.633 15618 2.064 1.288 2.075 2.527 2.239 1.745 3.772 3.393 15654 2.340 0.001 0.001 2.927 4.830 1.708 1.651 1.586

TABLE 117 SEQ ID NO P268 P278 P295 P339 P341 P356 P360 P392 13288 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 13292 1.194 1.000 1.000 1.474 3.006 2.766 1.622 10.061 13397 2.953 2.030 8.118 1.000 2.854 1.000 1000.000 0.001 13409 1000.000 1.332 1.000 0.344 1.537 1.000 0.001 0.464 13418 2.953 2.030 8.118 1.000 2.854 1.000 1000.000 0.001 13425 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 13516 1.422 2.018 2.385 1.218 2.039 3.486 1.636 1.623 13542 1.268 1.563 1.870 2.056 6.240 6.491 2.230 1.427 13543 1.000 1000.000 1.000 1.196 2.209 1000.000 0.001 1.000 13549 1.000 1.000 1.000 1.737 2.382 3.061 2.679 1.361 13568 1.000 1000.000 1.000 1.196 2.209 1000.000 0.001 1.000 13599 2.467 2.166 21.707 0.615 1.616 1.000 1.000 1.000 13623 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 13624 2.359 1.552 2.918 1.647 4.706 3.623 1.979 1.677 13651 2.953 2.030 8.118 1.000 2.854 1.000 1000.000 0.001 13659 2.467 2.166 21.707 0.615 1.616 1.000 1.000 1.000 13675 1.221 1.796 1.995 1.780 1.726 2.970 1.792 1.581 13676 1.221 1.796 1.995 1.780 1.726 2.970 1.792 1.581 13682 2.677 2.809 2.969 1.373 2.087 3.804 1.612 1.163 13691 2.468 5.262 4.008 1.487 4.366 2.078 1.781 1.332 13735 1000.000 1.332 1.000 0.344 1.537 1.000 0.001 0.464 13804 1.221 1.796 1.995 1.780 1.726 2.970 1.792 1.581 13808 2.565 1.856 1.000 1.000 2.449 1.000 2.097 2.647 13835 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 13927 1.369 1.000 1.000 1.679 3.084 2.855 2.104 0.927 13940 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 14009 1.412 1.431 3.103 1.000 2.847 2.621 1.000 1.117 14011 2.240 2.040 1.000 1.000 2.450 3.440 2.045 1.998 14014 1.837 2.201 2.518 1.604 2.248 2.989 1.570 1.409 14025 1.000 1.320 0.556 1.385 1.321 1.000 1.000 6.185 14027 0.713 1000.000 0.632 2.389 0.202 1.000 1.000 0.356 14080 1.000 1.320 0.556 1.385 1.321 1.000 1.000 6.185 14081 1.000 1.320 0.556 1.385 1.321 1.000 1.000 6.185 14115 2.151 2.384 2.417 0.573 1.451 2.652 1.000 0.734 14131 1.000 1.509 9.879 1000.000 2.327 0.001 1.236 0.870 14185 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 14224 1.000 1.509 9.879 1000.000 2.327 0.001 1.236 0.870 14225 1.657 1.732 3.510 1.652 4.946 4.071 2.194 1.932 14261 1.657 1.732 3.510 1.652 4.946 4.071 2.194 1.932 14305 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 14319 1.412 1.431 3.103 1.000 2.847 2.621 1.000 1.117 14320 1.657 1.732 3.510 1.652 4.946 4.071 2.194 1.932 14505 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 14562 0.718 1.000 1.000 1.675 2.301 1.361 2.161 1.825 14583 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 14601 0.789 1.609 1.000 0.797 1.000 2.075 2.491 2.505 14604 2.359 1.552 2.918 1.647 4.706 3.623 1.979 1.677 14688 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 14689 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 14690 1.864 1.428 2.631 1.854 3.430 3.182 1.892 1.581 14747 1.864 1.428 2.631 1.854 3.430 3.182 1.892 1.581 14824 2.495 2.090 3.320 1.000 3.907 2.976 1.875 1.000 14849 1.422 2.018 2.385 1.218 2.039 3.486 1.636 1.623 14870 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 14909 1.268 1.563 1.870 2.056 6.240 6.491 2.230 1.427 14927 2.183 2.285 3.554 1.247 2.093 1.840 1.855 1.504 14949 2.495 2.090 3.320 1.000 3.907 2.976 1.875 1.000 15014 2.006 1.696 2.261 1.611 2.154 3.791 1.816 1.356 15117 1.535 2.851 4.154 2.055 6.047 4.103 3.367 2.029 15147 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 15150 2.274 1.266 4.526 2.591 5.409 3.138 2.675 1.391 15159 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 15279 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 15293 1.971 1.699 2.355 1.453 3.122 2.528 1.949 1.326 15299 1.422 2.018 2.385 1.218 2.039 3.486 1.636 1.623 15341 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 15347 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 15373 2.516 0.852 1.775 0.818 4.294 2.281 1.119 0.890 15379 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 15408 1.794 1.486 5.006 0.398 4.768 0.001 2.344 2.434 15413 2.079 1.664 1.000 1.871 2.812 2.693 5.094 1.947 15453 2.325 2.043 2.530 2.411 5.749 5.509 3.490 2.008 15455 1.000 1.320 0.556 1.385 1.321 1.000 1.000 6.185 15460 1.677 2.420 2.263 1.314 1.473 2.523 1.776 2.244 15470 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 15476 1.977 1.676 1.774 1.542 2.538 1.867 2.312 1.000 15490 2.942 0.729 1.772 0.861 15.794 2.349 1.363 0.808 15494 1.457 1.690 2.551 1.860 4.114 3.548 3.125 0.792 15519 1.187 1.447 1.000 1.484 3.621 3.844 1.995 1.313 15525 1.586 1.943 1.000 0.699 1.593 2.039 1.798 0.774 15535 2.157 1.922 3.895 4.143 2.655 1.914 2.159 3.312 15537 3.442 3.933 5.994 1.448 8.695 7.488 2.687 2.449 15551 2.467 1.000 7.584 1.417 3.693 1.947 1.539 4.429 15564 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 15570 1.000 2.819 1.000 1.589 1.238 1.784 0.748 2.486 15577 1.422 2.018 2.385 1.218 2.039 3.486 1.636 1.623 15579 2.485 2.369 1.000 1.820 3.354 5.046 1.820 0.703 15583 3.203 1.593 4.012 1.593 6.374 6.940 3.158 0.947 15584 1.268 1.563 1.870 2.056 6.240 6.491 2.230 1.427 15586 1.422 2.018 2.385 1.218 2.039 3.486 1.636 1.623 15597 2.439 1.482 2.156 1.390 3.500 3.654 1.655 0.771 15618 2.448 2.617 4.003 1.289 2.940 3.894 2.277 1.202 15654 2.328 1.359 9.253 0.383 1.835 0.001 1.000 0.714

TABLE 118 SEQ ID NO P393 P413 P505 P517 P534 P546 P577 P695 13288 1.058 2.471 1.583 1.726 0.506 1.431 2.632 5.930 13292 14.260 2.516 1.498 3.747 1.300 5.779 11.202 0.001 13397 1.000 0.001 1.000 1.000 0.001 1.000 3.303 1.000 13409 1.000 1.000 0.458 1.249 0.001 1000.000 0.702 1.000 13418 1.000 0.001 1.000 1.000 0.001 1.000 3.303 1.000 13425 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 13516 0.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 13542 1.348 2.222 2.506 1.355 1.670 2.535 1.556 8.411 13543 1.000 1.000 1000.000 1.477 1.645 1.000 1.389 1.000 13549 0.914 1.603 1.936 1.485 2.430 1.999 1.647 4.375 13568 1.000 1.000 1000.000 1.477 1.645 1.000 1.389 1.000 13599 1.000 1.000 1.436 0.517 1.000 1.469 1.000 1.000 13623 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 13624 1.224 3.432 2.806 1.328 2.470 2.592 1.929 6.973 13651 1.000 0.001 1.000 1.000 0.001 1.000 3.303 1.000 13659 1.000 1.000 1.436 0.517 1.000 1.469 1.000 1.000 13675 1.241 1.841 1.470 1.000 1.672 2.218 1.649 7.555 13676 1.241 1.841 1.470 1.000 1.672 2.218 1.649 7.555 13682 1.258 2.153 1.849 1.445 1.000 1.531 1.637 3.302 13691 1.000 1.327 2.871 1.116 1.903 2.200 2.644 0.001 13735 1.000 1.000 0.458 1.249 0.001 1000.000 0.702 1.000 13804 1.241 1.841 1.470 1.000 1.672 2.218 1.649 7.555 13808 1.560 1.982 2.159 1.278 1.425 1.204 3.046 2.068 13835 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 13927 0.763 1.602 2.797 1.265 2.765 2.236 2.548 5.071 13940 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 14009 2.102 1.689 4.429 0.830 1.000 1.000 2.108 2.208 14011 1.935 1.911 2.812 1.000 1.854 1.793 2.441 0.001 14014 1.320 1.404 1.553 1.000 1.957 1.816 2.156 3.745 14025 1.219 2.547 1.288 2.539 3.936 3.625 2.363 1.955 14027 0.851 0.750 0.815 0.258 0.712 1.229 0.190 1.000 14080 1.219 2.547 1.288 2.539 3.936 3.625 2.363 1.955 14081 1.219 2.547 1.288 2.539 3.936 3.625 2.363 1.955 14115 2.765 1.000 2.202 0.472 0.490 1.417 0.725 0.001 14131 1.000 1.000 1.000 1.000 1.000 1.530 0.769 1.000 14185 1.058 2.471 1.583 1.726 0.506 1.431 2.632 5.930 14224 1.000 1.000 1.000 1.000 1.000 1.530 0.769 1.000 14225 1.322 2.608 1.910 1.199 1.635 1.893 1.473 5.842 14261 1.322 2.608 1.910 1.199 1.635 1.893 1.473 5.842 14305 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 14319 2.102 1.689 4.429 0.830 1.000 1.000 2.108 2.208 14320 1.322 2.608 1.910 1.199 1.635 1.893 1.473 5.842 14505 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 14562 1.000 1.518 1.980 1.518 2.526 1.588 1.865 2.251 14583 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 14601 0.743 2.126 1.613 1.177 2.128 1.000 1.951 6.931 14604 1.224 3.432 2.806 1.328 2.470 2.592 1.929 6.973 14688 1.058 2.471 1.583 1.726 0.506 1.431 2.632 5.930 14689 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 14690 1.205 3.301 2.749 1.256 2.474 2.345 1.826 8.108 14747 1.205 3.301 2.749 1.256 2.474 2.345 1.826 8.108 14824 1.000 1.793 2.719 1.679 1.000 1.549 2.076 0.001 14849 0.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 14870 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 14909 1.348 2.222 2.506 1.355 1.670 2.535 1.556 8.411 14927 2.809 1.534 1.366 1.197 2.545 1.964 1.506 0.001 14949 1.000 1.793 2.719 1.679 1.000 1.549 2.076 0.001 15014 1.249 2.009 1.832 1.488 1.379 1.975 2.128 13.930 15117 1.781 2.929 2.183 2.759 3.853 3.092 2.051 7.549 15147 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 15150 1.000 3.187 2.564 0.756 1.226 3.841 3.201 16.724 15159 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 15279 1.058 2.471 1.583 1.726 0.506 1.431 2.632 5.930 15293 1.952 1.472 1.917 1.516 2.305 2.677 2.620 2.660 15299 0.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 15341 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 15347 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 15373 0.537 1.790 0.727 0.750 0.329 1.100 1.239 0.001 15379 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 15408 0.852 1.789 3.765 0.686 3.176 1.591 1.852 0.001 15413 2.044 17.760 4.034 1.988 0.026 3.908 2.394 42.662 15453 1.088 5.833 3.519 1.572 2.641 4.011 1.695 7.783 15455 1.219 2.547 1.288 2.539 3.936 3.625 2.363 1.955 15460 1.710 2.337 1.898 0.892 1.347 1.908 1.136 3.404 15470 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 15476 1.000 3.033 1.912 1.699 2.147 2.780 2.155 2.518 15490 0.337 2.339 0.768 0.563 0.359 1.242 1.492 1.000 15494 1.000 2.266 2.040 1.000 2.747 2.620 1.718 14.145 15519 1.137 2.268 2.414 1.382 2.107 2.210 2.384 5.256 15525 1.243 1.766 1.547 0.843 1.000 1.498 2.122 4.421 15535 5.268 1.518 2.253 3.678 0.766 1.565 1.000 1.853 15537 0.815 2.497 3.234 2.275 2.344 3.596 5.023 12.124 15551 1.128 0.885 1.237 1.434 3.327 3.206 1.355 0.001 15564 1.058 2.471 1.583 1.726 0.506 1.431 2.632 5.930 15570 1.058 2.471 1.583 1.726 0.506 1.431 2.632 5.930 15577 0.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 15579 1.240 2.239 2.841 1.000 2.270 2.614 0.583 5.244 15583 0.633 2.821 2.976 1.253 1.675 3.657 2.284 8.587 15584 1.348 2.222 2.506 1.355 1.670 2.535 1.556 8.411 15586 0.741 2.181 2.494 1.504 1.511 1.831 2.064 4.421 15597 1.000 1.801 1.978 1.000 3.188 1.607 2.276 13.068 15618 0.790 3.524 3.377 2.062 2.123 1.959 1.626 1.000 15654 0.001 1.346 1.831 1.000 1.646 1.944 1.549 1.000

TABLE 119 SEQ ID NO P784 P786 P791 P888 P889 13288 1.000 1.000 4.202 1.464 2.147 13292 1.000 1.276 14.034 4.139 3.640 13397 1.708 2.247 1.000 0.441 0.001 13409 1.391 1.857 1.000 0.402 1.000 13418 1.708 2.247 1.000 0.441 0.001 13425 1.328 1.421 2.456 1.910 2.069 13516 1.243 1.679 2.228 2.333 1.774 13542 0.819 1.632 2.808 5.465 2.307 13543 1000.000 0.758 1.000 1.000 1.000 13549 1.000 1.000 1.834 2.776 1.636 13568 1000.000 0.758 1.000 1.000 1.000 13599 1.000 1.000 1.000 0.642 1.000 13623 1.328 1.421 2.456 1.910 2.069 13624 1.000 1.416 2.862 2.690 1.645 13651 1.708 2.247 1.000 0.441 0.001 13659 1.000 1.000 1.000 0.642 1.000 13675 1.000 1.821 1.628 2.276 2.501 13676 1.000 1.821 1.628 2.276 2.501 13682 1.000 1.888 1.915 2.276 1.481 13691 3.336 1.677 2.208 1.000 1.976 13735 1.391 1.857 1.000 0.402 1.000 13804 1.000 1.821 1.628 2.276 2.501 13808 1.000 1.629 2.152 1.000 1.792 13835 1.328 1.421 2.456 1.910 2.069 13927 1.000 1.997 2.083 3.178 3.444 13940 1.000 1.780 1.000 2.177 2.258 14009 1.356 0.696 1.000 1.000 1.463 14011 2.324 1.000 2.379 1.407 2.833 14014 2.137 1.934 2.482 2.035 3.980 14025 0.796 1.000 1.737 1.000 2.218 14027 2.531 3.138 0.395 1.000 1.000 14080 0.796 1.000 1.737 1.000 2.218 14081 0.796 1.000 1.737 1.000 2.218 14115 1000.000 1.984 1000.000 1.374 1.000 14131 3.031 1.000 1.000 1.000 1.000 14185 1.000 1.000 4.202 1.464 2.147 14224 3.031 1.000 1.000 1.000 1.000 14225 0.876 1.781 2.424 4.143 1.977 14261 0.876 1.781 2.424 4.143 1.977 14305 1.000 1.780 1.000 2.177 2.258 14319 1.356 0.696 1.000 1.000 1.463 14320 0.876 1.781 2.424 4.143 1.977 14505 1.328 1.421 2.456 1.910 2.069 14562 1.000 1.000 1.992 2.144 1.615 14583 1.000 1.780 1.000 2.177 2.258 14601 1.290 1.000 1.000 1.995 2.203 14604 1.000 1.416 2.862 2.690 1.645 14688 1.000 1.000 4.202 1.464 2.147 14689 1.328 1.421 2.456 1.910 2.069 14690 0.816 1.000 2.196 2.446 1.518 14747 0.816 1.000 2.196 2.446 1.518 14824 1.585 1.889 2.178 1.806 1.867 14849 1.243 1.679 2.228 2.333 1.774 14870 1.328 1.421 2.456 1.910 2.069 14909 0.819 1.632 2.808 5.465 2.307 14927 2.810 2.638 1.976 1.491 2.955 14949 1.585 1.889 2.178 1.806 1.867 15014 1.253 1.994 1.874 3.193 2.663 15117 1.559 2.762 5.043 4.135 3.753 15147 1.328 1.421 2.456 1.910 2.069 15150 1.306 1.940 2.293 3.897 1.624 15159 1.328 1.421 2.456 1.910 2.069 15279 1.000 1.000 4.202 1.464 2.147 15293 1.511 1.357 1.632 1.891 1.895 15299 1.243 1.679 2.228 2.333 1.774 15341 1.000 1.780 1.000 2.177 2.258 15347 1.000 1.780 1.000 2.177 2.258 15373 0.573 2.678 1.000 2.507 3.278 15379 1.000 1.780 1.000 2.177 2.258 15408 7.866 1.000 1000.000 1.719 1.000 15413 2.625 2.744 4.155 2.105 4.438 15453 1.000 2.139 3.014 3.159 3.381 15455 0.796 1.000 1.737 1.000 2.218 15460 1.000 1.780 1.000 2.177 2.258 15470 1.328 1.421 2.456 1.910 2.069 15476 1.489 2.750 2.910 5.049 4.006 15490 0.419 3.014 0.575 2.397 3.558 15494 1.000 1.815 2.513 3.487 2.180 15519 1.328 1.421 2.456 1.910 2.069 15525 1.000 1.493 2.186 1.000 2.222 15535 1.267 3.638 1.623 5.889 3.339 15537 1.746 2.363 5.515 2.674 3.637 15551 2.399 3.587 3.625 2.567 2.417 15564 1.000 1.000 4.202 1.464 2.147 15570 1.000 1.000 4.202 1.464 2.147 15577 1.243 1.679 2.228 2.333 1.774 15579 0.397 1.000 1.472 5.315 2.250 15583 1.000 1.939 2.505 4.525 2.674 15584 0.819 1.632 2.808 5.465 2.307 15586 1.243 1.679 2.228 2.333 1.774 15597 1.295 1.658 2.836 2.766 2.873 15618 2.167 2.157 3.410 2.828 3.794 15654 1.352 1.000 2.727 0.583 1.000

In general, a polynucleotide is said to represent a significantly differentially expressed gene between two samples when there is detectable levels of expression in at least one sample and the ratio value is greater than at least about 1.2 fold, preferably greater than at least about 1.5 fold, more preferably greater than at least about 2 fold, where the ratio value is calculated using the method described above.

A differential expression ratio of 1 indicates that the expression level of the gene in the tumor cell was not statistically different from expression of that gene in normal colon cells of the same patient. A differential expression ratio significantly greater than 1 in cancerous colon cells relative to normal colon cells indicates that the gene is increased in expression in cancerous cells relative to normal cells, indicating that the gene plays a role in the development of the cancerous phenotype, and may be involved in promoting metastasis of the cell. Detection of gene products from such genes can provide an indicator that the cell is cancerous, and may provide a therapeutic and/or diagnostic target.

Likewise, a differential expression ratio significantly less than 1 in cancerous colon cells relative to normal colon cells indicates that, for example, the gene is involved in suppression of the cancerous phenotype. Increasing activity of the gene product encoded by such a gene, or replacing such activity, can provide the basis for chemotherapy. Such gene can also serve as markers of cancerous cells, e.g., the absence or decreased presence of the gene product in a colon cell relative to a normal colon cell indicates that the cell may be cancerous.

Example 76 Functional Analysis of Gene Products Differentially Expressed in Cancer in Patients

The gene products of genes differentially expressed in cancerous cells are further analyzed to confirm the role and function of the gene product in tumorgenesis, e.g., in promoting or inhibiting development of a metastatic phenotype.

Blocking Expression of Gene Products Using Antisense

The effect of single genes upon development of cancer is assessed through use of antisense oligonucleotides specific for sequences corresponding to a selected sequence. Antisense oligonucleotides are prepared based upon a selected sequence that corresponds to a gene of interest. The antisense oligonucleotide is introduced into a test cell and the effect upon expression of the corresponding gene, as well as the effect upon a phenotype of interest assessed (e.g., a normal cell is examined for induction of the cancerous phenotype, or a cancerous cell is examined for suppression of a cancerous phenotype (e.g., suppression of metastasis)).

Blocking Function of Gene Products Using Gene Product-Specific Antibodies and/or Small Molecule Inhibitors

The function of gene products corresponding to genes/clusters identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted, blocking antibodies can generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype. In order to generate antibodies, a clone corresponding to a selected gene product/cluster is selected, and a sequence that represents a partial or complete coding sequence is obtained. The resulting clone is then expressed, the polypeptide produced isolated, and antibodies generated. The antibodies are then combined with cells and the effect upon tumorigenesis assessed.

Where the gene product of the gene/clusters identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecule that inhibit or enhance function of the corresponding protein or protein family.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Deposit Information. The following materials were deposited with the American Type Culture Collection (CMCC=Chiron Master Culture Collection).

TABLE 111 Cell Lines Deposited with ATCC ATCC CMCC Cell Line Deposit Date Accession No. Accession No. KM12L4 Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containing specific clones, were assigned an “ES” number (internal reference) and deposited with the ATCC. Table 112 (inserted before the claims) provides the ATCC Accession Nos. and internal references (CMCC Nos.) of the ES deposits, all of which were deposited on or before the filing date of the present application. The names of the clones contained within each of these deposits are provided in Table 113 (inserted before the claims).

TABLE 112 ES # CMCC# ATCC Deposit# 85 5175 PTA-1313 86 5176 PTA-1314 87 5177 PTA-1315 88 5178 PTA-1316 89 5179 PTA-1317 90 5180 PTA-1318 91 5181 PTA-1319 92 5182 PTA-1320 93 5183 PTA-1321 94 5184 PTA-1322 95 5185 PTA-1323 96 5186 PTA-1324 97 5187 PTA-1325 98 5188 PTA-1326 99 5189 PTA-1327 100 5190 PTA-1328 101 5191 PTA-1329 102 5192 PTA-1330 103 5193 PTA-1331 104 5194 PTA-1332 105 5195 PTA-1333 106 5196 PTA-1334 107 5197 PTA-1335 108 5198 PTA-1336 109 5199 PTA-1372 110 5200 PTA-1373 111 5201 PTA-1374 112 5202 PTA-1375 113 5203 PTA-1376 114 5204 PTA-1377 115 5205 PTA-1378 116 5206 PTA-1379 117 5207 PTA-1380 118 5208 PTA-1381 122 5212 PTA-1382 123 5213 PTA-1383 124 5214 PTA-1384 125 5215 PTA-1385 126 5216 PTA-1386 127 5217 PTA-1387 128 5218 PTA-1388 129 5219 PTA-1389 130 5220 PTA-1390 131 5221 PTA-1391 132 5222 PTA-1392 133 5223 PTA-1393 134 5209 PTA-1431 135 5210 PTA-1432 136 5238 PTA-1497

TABLE 113 ES No. Clone Name ES 85 M00057077B:D02 ES 85 M00057078D:C12 ES 85 M00057079D:E09 ES 85 M00057080C:C02 ES 85 M00057085A:A03 ES 85 M00057088B:C02 ES 85 M00057091A:C03 ES 85 M00057091A:C04 ES 85 M00057091C:E12 ES 85 M00057093B:F09 ES 85 M00057099C:C08 ES 85 M00057100C:E09 ES 85 M00057100D:B03 ES 85 M00057103A:E11 ES 85 M00057103A:H09 ES 85 M00057104B:F08 ES 85 M00057106B:A03 ES 85 M00057106C:E02 ES 85 M00057106D:B06 ES 85 M00057108B:F04 ES 85 M00057108D:E09 ES 85 M00057108D:E09 ES 85 M00057112D:B09 ES 85 M00057114D:B10 ES 85 M00057117D:G11 ES 85 M00057118C:C02 ES 85 M00057120D:E12 ES 85 M00057124B:D10 ES 85 M00057127A:F11 ES 85 M00057127B:G07 ES 85 M00057130C:H11 ES 85 M00057131C:B01 ES 85 M00057132C:F08 ES 85 M00057133D:F01 ES 85 M00057134A:C01 ES 85 M00057134C:A01 ES 85 M00057134D:G10 ES 85 M00057135D:H04 ES 85 M00057136A:F01 ES 85 M00057141B:B02 ES 85 M00057141D:D02 ES 85 M00057142A:A07 ES 85 M00057143C:E05 ES 85 M00057145A:D05 ES 85 M00057146D:C09 ES 85 M00057147A:A01 ES 85 M00057150A:C10 ES 85 M00057151A:B04 ES 86 M00057154A:D06 ES 86 M00057154C:B04 ES 86 M00057161B:E09 ES 86 M00057162A:C07 ES 86 M00057162B:H02 ES 86 M00057162D:D10 ES 86 M00057163D:B01 ES 86 M00057165D:E12 ES 86 M00057167B:E12 ES 86 M00057167B:G12 ES 86 M00057167D:B07 ES 86 M00057170C:H03 ES 86 M00057174B:C06 ES 86 M00057174B:G12 ES 86 M00057174C:H12 ES 86 M00057180A:H11 ES 86 M00057181C:D06 ES 86 M00057182D:B11 ES 86 M00057189B:G05 ES 86 M00057191A:A03 ES 86 M00057192B:E02 ES 86 M00057192D:G02 ES 86 M00057196A:E03 ES 86 M00057196C:F04 ES 86 M00057203C:E06 ES 86 M00057208A:A02 ES 86 M00057208C:C06 ES 86 M00057208C:D08 ES 86 M00057211B:F07 ES 86 M00057211D:A06 ES 86 M00057215B:B02 ES 86 M00057217B:B07 ES 86 M00057218D:C01 ES 86 M00057223C:C06 ES 86 M00057224B:C10 ES 86 M00057226D:C05 ES 86 M00057229D:F06 ES 86 M00057230C:D12 ES 86 M00057231C:G09 ES 86 M00057231D:A09 ES 86 M00057232B:D06 ES 86 M00057233A:F07 ES 86 M00057233B:E04 ES 86 M00057236B:H06 ES 86 M00057237A:B11 ES 86 M00057239A:G08 ES 86 M00057241B:B04 ES 86 M00057242B:F07 ES 87 M00057242D:B09 ES 87 M00057242D:H05 ES 87 M00057249A:C06 ES 87 M00057259A:H10 ES 87 M00057259B:B08 ES 87 M00057266C:D04 ES 87 M00057266C:G12 ES 87 M00057268C:E10 ES 87 M00057270B:H09 ES 87 M00057270C:E04 ES 87 M00057271C:E01 ES 87 M00057272A:B03 ES 87 M00057272C:H04 ES 87 M00057272D:A01 ES 87 M00057275B:A12 ES 87 M00057277B:C09 ES 87 M00057277B:E10 ES 87 M00057279A:G02 ES 87 M00057280C:A06 ES 87 M00057283A:E06 ES 87 M00057288D:E08 ES 87 M00057291C:B06 ES 87 M00057297A:F03 ES 87 M00057300B:F02 ES 87 M00057301B:H12 ES 87 M00057304A:E01 ES 87 M00057306B:H07 ES 87 M00057312B:E11 ES 87 M00057318B:B09 ES 87 M00057318C:A03 ES 87 M00057324A:D12 ES 87 M00057325C:C10 ES 87 M00057333A:F09 ES 87 M00057334B:F01 ES 87 M00057337B:G02 ES 87 M00057340B:C12 ES 87 M00042355A:G02 ES 87 M00042355D:C01 ES 87 M00042442D:A02 ES 87 M00042444D:G05 ES 87 M00042444D:H08 ES 87 M00042450D:H10 ES 87 M00042453C:E01 ES 87 M00042460D:A07 ES 87 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M00056969B:C08 ES 132 M00056969D:B01 ES 132 M00056972A:F05 ES 132 M00056973D:B08 ES 132 M00056974C:F04 ES 132 M00056976C:F10 ES 132 M00056977A:G03 ES 132 M00056985B:C05 ES 132 M00056986A:F11 ES 132 M00056986D:G01 ES 132 M00056990C:B09 ES 132 M00056990D:C11 ES 132 M00056993A:B06 ES 132 M00056993D:D03 ES 132 M00056994B:F07 ES 133 M00056994C:C03 ES 133 M00056996D:A12 ES 133 M00056997C:H09 ES 133 M00056998A:E08 ES 133 M00057002D:B05 ES 133 M00057002D:B06 ES 133 M00057003B:B09 ES 133 M00057005B:C01 ES 133 M00057005C:D03 ES 133 M00057007C:B12 ES 133 M00057008C:E09 ES 133 M00057011A:D03 ES 133 M00057013B:D01 ES 133 M00057015A:C12 ES 133 M00057019C:H02 ES 133 M00057023A:H09 ES 133 M00057024A:E02 ES 133 M00057024A:G05 ES 133 M00057024D:H08 ES 133 M00057025C:A08 ES 133 M00057027C:G06 ES 133 M00057028D:D09 ES 133 M00057029A:C12 ES 133 M00057029D:A06 ES 133 M00057033A:F09 ES 133 M00057035B:C09 ES 133 M00057041D:B11 ES 133 M00057044C:F06 ES 133 M00057047B:C02 ES 133 M00057049A:G06 ES 133 M00057049C:H05 ES 133 M00057052D:B11 ES 133 M00057052D:G09 ES 133 M00057055B:G08 ES 133 M00057055B:G08 ES 133 M00057058C:F09 ES 133 M00057059D:F06 ES 133 M00057059D:H09 ES 133 M00057060B:A12 ES 133 M00057061C:D04 ES 133 M00057063A:C08 ES 133 M00057065C:D04 ES 133 M00057066A:A04 ES 133 M00057070D:B08 ES 133 M00057072B:E02 ES 133 M00057073D:A05 ES 133 M00057074D:C09 ES 133 M00057074D:C09 ES 134 M00055909B:G01 ES 134 M00055909C:E08 ES 134 M00055911B:E06 ES 134 M00055912C:E10 ES 134 M00055912D:C05 ES 134 M00055913B:D05 ES 134 M00055919A:A06 ES 134 M00055921A:E03 ES 134 M00055921B:B11 ES 134 M00055922A:C02 ES 134 M00055924A:H11 ES 134 M00055930A:B08 ES 134 M00055931A:A03 ES 134 M00055931A:C01 ES 134 M00055931B:E01 ES 134 M00055936B:E07 ES 134 M00055937B:C02 ES 134 M00055941B:B12 ES 134 M00055941B:B12 ES 134 M00055945A:H11 ES 134 M00055945B:E10 ES 134 M00055946D:G07 ES 134 M00055951C:C02 ES 134 M00055956C:E02 ES 134 M00055958D:F02 ES 134 M00055959D:A12 ES 134 M00055966C:A03 ES 134 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M00056077D:E12 ES 136 M00056079B:D12 ES 136 M00056079B:F07 ES 136 M00056079C:C11 ES 136 M00056081D:B05 ES 136 M00056081D:B09 ES 136 M00056082C:F06 ES 136 M00056085D:H11 ES 136 M00056094A:H07 ES 136 M00056098A:H01 ES 136 M00056099B:G09 ES 136 M00056099B:H11 ES 136 M00056099B:H11 ES 136 M00056103A:D12 ES 136 M00056103C:H12 ES 136 M00056107B:E06 ES 136 M00056108D:B12 ES 136 M00056108D:B12 ES 136 M00056110C:D09 ES 136 M00056111D:H02 ES 136 M00056112A:H02 ES 136 M00056114C:C06 ES 136 M00056125B:D09 ES 136 M00056128C:B10 ES 136 M00056131B:C12 ES 136 M00056133D:D09 ES 136 M00056136A:B11

The above material has been deposited with the American Type Culture Collection, Rockville, Md., under the accession number indicated. These deposits will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. The deposit will be maintained for a period of at least 30 years following issuance of this patent, or for the enforceable life of the patent, whichever is greater. Upon the granting of a patent, all restrictions on the availability to the public of the deposited material will be irrevocably removed.

The deposits described herein are provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where the ATCC deposit is composed of a pool of cDNA clones or a library of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones in the pool or library were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

Example 77 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from mRNA isolated from the GRRpz or and WOca cells, which were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz cells were primary cells derived from normal prostate epithelium. The WOca cells were prostate epithelial cells derived from prostate cancer Gleason Grade 4+4. Polynucleotides expressed by these cells were isolated and analyzed; the sequences of these polynucleotides were about 275-300 nucleotides in length.

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. The remaining sequences were then used in a BLASTN vs. GenBank search; sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the GenBank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded. Second, a BLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p value less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 316 sequences listed as SEQ ID NOS:15667-15982 in the accompanying Sequence Listing and summarized in Table 120 (inserted prior to claims). Each identified polynucleotide represents sequence from at least a partial mRNA transcript. Many of the sequences include the sequence ggcacgag at the 5′ end; this sequence is a sequencing artifact and not part of the sequence of the polynucleotides of the invention.

Table 120 provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for use in the present specification; 2) the Cluster Identification No. (“CLUSTER”); 3) the sequence name (“SEQ NAME”) used as an internal identifier of the sequence; 4) the orientation of the sequence (“ORIENT”); 5) the name assigned to the clone from which the sequence was isolated (“CLONE ID”); and the name of the library from which the sequence was isolated (“LIBRARY”). CH22PRC indicates the sequence was isolated from Library 22; CH21PRN indicates the sequence was isolated from Library 21. A description of the libraries is provided in Table 122 below. Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene.

Example 78 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS: 15667-15982 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in either the GenBank (nucleotide sequences) or Non-Redundant Protein (amino acid sequences) databases. Query and individual sequences were aligned using the BLAST 2.0 programs, available over the world wide web at a site sponsored by the National Center for Biotechnology Information, which is supported by the National Library of Medicine and the National Institutes of Health (see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above in Example 77.

Table 121 (inserted before the claims) provide the alignment summaries having a p value of 1×10⁻² or less indicating substantial homology between the sequences of the present invention and those of the indicated public databases. Specifically, Table 121 provides the SEQ ID NO of the query sequence, the accession number of the GenBank database entry of the homologous sequence, and the p value of the alignment. Table 121 also provides the SEQ ID NO of the query sequence, the accession number of the Non-Redundant Protein database entry of the homologous sequence, and the p value of the alignment. The alignments provided in Table 121 are the best available alignment to a DNA or amino acid sequence at a time just prior to filing of the present specification. The activity of the polypeptide encoded by the SEQ ID NOS listed in Table 121 can be extrapolated to be substantially the same or substantially similar to the activity of the reported nearest neighbor or closely related sequence. The accession number of the nearest neighbor is reported, providing a publicly available reference to the activities and functions exhibited by the nearest neighbor. The public information regarding the activities and functions of each of the nearest neighbor sequences is incorporated by reference in this application. Also incorporated by reference is all publicly available information regarding the sequence, as well as the putative and actual activities and functions of the nearest neighbor sequences listed in Table 121 and their related sequences. The search program and database used for the alignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of the corresponding polynucleotide. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of the corresponding polynucleotides.

TABLE 120 SEQ ID CLUSTER SEQ NAME ORIENT CLONE ID LIBRARY 15667 819545 RTA22200265F.k.06.1.P.Seq F M00064554D:A03 CH22PRC 15668 377944 RTA22200251F.j.02.1.P.Seq F M00063482A:A08 CH21PRN 15669 818497 RTA22200252F.a.13.1.P.Seq F M00063514C:D03 CH21PRN 15670 819498 RTA22200252F.n.05.1.P.Seq F M00063638C:G12 CH21PRN 15671 455465 RTA22200264F.e.16.1.P.Seq F M00064454A:H10 CH22PRC 15672 819069 RTA22200255F.f.01.1.P.Seq F M00063940D:F09 CH21PRN 15673 672003 RTA22200265F.b.09.1.P.Seq F M00064517C:F11 CH22PRC 15674 728115 RTA22200253F.o.24.1.P.Seq F M00063838B:G08 CH21PRN 15675 372700 RTA22200260F.b.20.1.P.Seq F M00063580C:A06 CH22PRC 15676 818056 RTA22200266F.c.13.1.P.Seq F M00064593D:C01 CH22PRC 15677 818497 RTA22200255F.a.17.1.P.Seq F M00063920D:H02 CH21PRN 15678 729832 RTA22200267F.l.21.1.P.Seq F M00064714A:G03 CH22PRC 15679 505514 RTA22200251F.b.21.1.P.Seq F M00063158A:A01 CH21PRN 15680 376488 RTA22200254F.c.05.1.P.Seq F M00063852B:D08 CH21PRN 15681 376488 RTA22200260F.b.09.1.P.Seq F M00063578C:A06 CH22PRC 15682 748572 RTA22200254F.c.07.1.P.Seq F M00063852D:F07 CH21PRN 15683 549934 RTA22200253F.k.18.1.P.Seq F M00063801B:D04 CH21PRN 15684 819069 RTA22200255F.e.24.1.P.Seq F M00063940D:F09 CH21PRN 15685 817618 RTA22200253F.n.16.1.P.Seq F M00063828D:E05 CH21PRN 15686 124396 RTA22200263F.a.11.2.P.Seq F M00064375B:G07 CH22PRC 15687 404375 RTA22200260F.m.08.1.P.Seq F M00063967D:G02 CH22PRC 15688 391820 RTA22200261F.f.02.1.P.Seq F M00064000B:C03 CH22PRC 15689 672003 RTA22200267F.i.06.1.P.Seq F M00064693D:F08 CH22PRC 15690 830620 RTA22200263F.n.09.1.P.Seq F M00064424B:C12 CH22PRC 15691 450399 RTA22200251F.f.23.1.P.Seq F M00063467D:H07 CH21PRN 15692 450982 RTA22200261F.n.18.1.P.Seq F M00064307B:G02 CH22PRC 15693 819894 RTA22200264F.h.18.1.P.Seq F M00064467B:D06 CH22PRC 15694 379302 RTA22200257F.j.02.3.P.Seq F M00064178C:C04 CH21PRN 15695 379746 RTA22200256F.e.16.1.P.Seq F M00064086C:E01 CH21PRN 15696 124863 RTA22200265F.m.06.1.P.Seq F M00064564A:C02 CH22PRC 15697 379154 RTA22200257F.c.11.1.P.Seq F M00064151B:C07 CH21PRN 15698 830620 RTA22200262F.l.23.1.P.Seq F M00064358C:D09 CH22PRC 15699 389409 RTA22200266F.l.24.1.P.Seq F M00064631A:C07 CH22PRC 15700 397284 RTA22200262F.i.22.1.P.Seq F M00064346C:B09 CH22PRC 15701 819440 RTA22200264F.e.19.1.P.Seq F M00064454C:B06 CH22PRC 15702 389409 RTA22200266F.m.01.1.P.Seq F M00064631A:C07 CH22PRC 15703 518848 RTA22200265F.n.15.1.P.Seq F M00064571C:C04 CH22PRC 15704 830620 RTA22200263F.a.21.1.P.Seq F M00064376A:A05 CH22PRC 15705 379154 RTA22200256F.f.20.1.P.Seq F M00064090D:D09 CH21PRN 15706 818544 RTA22200256F.h.04.1.P.Seq F M00064105B:A03 CH21PRN 15707 817375 RTA22200251F.a.15.1.P.Seq F M00063152C:B07 CH21PRN 15708 455264 RTA22200259F.e.23.1.P.Seq F M00063539C:C11 CH22PRC 15709 817503 RTA22200266F.k.11.1.P.Seq F M00064624D:C09 CH22PRC 15710 377696 RTA22200256F.d.21.1.P.Seq F M00064082D:D10 CH21PRN 15711 375596 RTA22200261F.h.10.1.P.Seq F M00064009A:C01 CH22PRC 15712 817689 RTA22200263F.h.05.1.P.Seq F M00064399A:E01 CH22PRC 15713 831867 RTA22200262F.i.15.2.P.Seq F M00064345A:A03 CH22PRC 15714 830085 RTA22200261F.k.14.1.P.Seq F M00064293D:B12 CH22PRC 15715 389627 RTA22200264F.c.10.1.P.Seq F M00064447B:C06 CH22PRC 15716 397284 RTA22200259F.k.09.1.P.Seq F M00063555B:D01 CH22PRC 15717 380063 RTA22200261F.j.02.1.P.Seq F M00064014D:H05 CH22PRC 15718 830931 RTA22200266F.m.23.1.P.Seq F M00064633C:A03 CH22PRC 15719 819321 RTA22200257F.l.03.3.P.Seq F M00064194C:D02 CH21PRN 15720 475587 RTA22200261F.c.01.1.P.Seq F M00063990A:D05 CH22PRC 15721 819046 RTA22200255F.a.18.1.P.Seq F M00063920D:H05 CH21PRN 15722 817477 RTA22200253F.g.21.1.P.Seq F M00063784A:H12 CH21PRN 15723 475587 RTA22200261F.b.24.1.P.Seq F M00063990A:D05 CH22PRC 15724 728115 RTA22200253F.p.01.1.P.Seq F M00063838B:G08 CH21PRN 15725 389627 RTA22200260F.i.24.1.P.Seq F M00063957A:E02 CH22PRC 15726 403453 RTA22200256F.i.24.1.P.Seq F M00064113B:C04 CH21PRN 15727 508525 RTA22200255F.d.10.1.P.Seq F M00063931B:F07 CH21PRN 15728 819525 RTA22200261F.n.20.1.P.Seq F M00064307C:G03 CH22PRC 15729 817618 RTA22200255F.i.03.1.P.Seq F M00064025D:H12 CH21PRN 15730 819403 RTA22200254F.h.14.1.P.Seq F M00063888D:D05 CH21PRN 15731 553242 RTA22200254F.g.20.1.P.Seq F M00063886A:B06 CH21PRN 15732 817417 RTA22200255F.a.10.1.P.Seq F M00063919C:E07 CH21PRN 15733 817618 RTA22200252F.f.13.1.P.Seq F M00063604A:B11 CH21PRN 15734 611440 RTA22200262F.e.04.2.P.Seq F M00064328B:H09 CH22PRC 15735 817375 RTA22200260F.m.06.1.P.Seq F M00063967C:A12 CH22PRC 15736 213577 RTA22200255F.i.23.1.P.Seq F M00064033C:C11 CH21PRN 15737 820061 RTA22200265F.p.10.1.P.Seq F M00064579D:E11 CH22PRC 15738 455264 RTA22200259F.m.06.1.P.Seq F M00063559D:G03 CH22PRC 15739 455264 RTA22200255F.o.23.1.P.Seq F M00064059A:C11 CH21PRN 15740 380331 RTA22200255F.b.19.1.P.Seq F M00063926A:H04 CH21PRN 15741 380331 RTA22200252F.b.19.1.P.Seq F M00063518D:A01 CH21PRN 15742 817455 RTA22200267F.o.01.1.P.Seq F M00064723D:H03 CH22PRC 15743 423967 RTA22200252F.a.20.1.P.Seq F M00063515B:H02 CH21PRN 15744 220584 RTA22200261F.m.14.1.P.Seq F M00064302A:D10 CH22PRC 15745 817688 RTA22200251F.e.20.1.P.Seq F M00063462D:D07 CH21PRN 15746 549934 RTA22200253F.n.10.1.P.Seq F M00063826A:D03 CH21PRN 15747 819149 RTA22200255F.e.16.1.P.Seq F M00063938B:H07 CH21PRN 15748 817455 RTA22200267F.n.24.1.P.Seq F M00064723D:H03 CH22PRC 15749 377696 RTA22200251F.j.03.1.P.Seq F M00063482A:F07 CH21PRN 15750 830146 RTA22200260F.b.07.1.P.Seq F M00063578B:E02 CH22PRC 15751 194490 RTA22200264F.l.07.1.P.Seq F M00064481C:F03 CH22PRC 15752 819460 RTA22200257F.m.15.3.P.Seq F M00064200D:E08 CH21PRN 15753 819018 RTA22200257F.p.01.3.P.Seq F M00064212D:E04 CH21PRN 15754 830620 RTA22200259F.p.24.1.P.Seq F M00063571B:G03 CH22PRC 15755 141079 RTA22200262F.k.19.1.P.Seq F M00064354A:A10 CH22PRC 15756 376588 RTA22200256F.e.04.1.P.Seq F M00064083D:E05 CH21PRN 15757 380604 RTA22200264F.g.05.1.P.Seq F M00064460C:B01 CH22PRC 15758 413138 RTA22200260F.b.05.1.P.Seq F M00063577C:C02 CH22PRC 15759 818544 RTA22200265F.e.12.1.P.Seq F M00064527A:H07 CH22PRC 15760 647435 RTA22200257F.h.08.1.P.Seq F M00064172C:A02 CH21PRN 15761 551785 RTA22200266F.c.09.1.P.Seq F M00064593A:A05 CH22PRC 15762 17092 RTA22200261F.f.17.1.P.Seq F M00064002C:F06 CH22PRC 15763 818326 RTA22200251F.i.06.1.P.Seq F M00063478C:D01 CH21PRN 15764 377944 RTA22200262F.e.03.2.P.Seq F M00064328B:H04 CH22PRC 15765 745559 RTA22200262F.m.04.1.P.Seq F M00064359B:H12 CH22PRC 15766 818326 RTA22200265F.d.08.1.P.Seq F M00064524A:A09 CH22PRC 15767 379879 RTA22200264F.b.23.1.P.Seq F M00064446A:D11 CH22PRC 15768 819640 RTA22200257F.f.24.1.P.Seq F M00064165A:B12 CH21PRN 15769 818326 RTA22200265F.a.14.1.P.Seq F M00064514D:F11 CH22PRC 15770 243524 RTA22200265F.g.04.1.P.Seq F M00064532D:G06 CH22PRC 15771 43995 RTA22200261F.l.02.1.P.Seq F M00064294D:F01 CH22PRC 15772 597854 RTA22200262F.g.06.2.P.Seq F M00064337D:F01 CH22PRC 15773 268290 RTA22200260F.p.14.1.P.Seq F M00063981D:A06 CH22PRC 15774 818043 RTA22200256F.p.10.2.P.Seq F M00064138A:F11 CH21PRN 15775 830930 RTA22200267F.b.03.1.P.Seq F M00064652B:D09 CH22PRC 15776 389627 RTA22200260F.j.01.1.P.Seq F M00063957A:E02 CH22PRC 15777 378730 RTA22200260F.i.07.1.P.Seq F M00063955C:F07 CH22PRC 15778 819037 RTA22200260F.n.09.1.P.Seq F M00063972C:E10 CH22PRC 15779 830397 RTA22200261F.g.14.1.P.Seq F M00064005D:A08 CH22PRC 15780 450247 RTA22200261F.e.10.1.P.Seq F M00063998C:E09 CH22PRC 15781 819273 RTA22200252F.b.09.1.P.Seq F M00063517A:A04 CH21PRN 15782 587779 RTA22200257F.i.11.3.P.Seq F M00064175B:B09 CH21PRN 15783 818639 RTA22200256F.j.09.1.P.Seq F M00064115B:E12 CH21PRN 15784 615617 RTA22200261F.o.13.1.P.Seq F M00064309C:H09 CH22PRC 15785 79309 RTA22200257F.j.13.3.P.Seq F M00064180A:G03 CH21PRN 15786 748994 RTA22200261F.o.20.1.P.Seq F M00064310C:A10 CH22PRC 15787 818682 RTA22200258F.h.07.1.P.Seq F M00064271B:D03 CH21PRN 15788 373061 RTA22200253F.j.09.1.P.Seq F M00063795C:D09 CH21PRN 15789 484413 RTA22200253F.g.09.1.P.Seq F M00063781B:B10 CH21PRN 15790 819273 RTA22200258F.h.04.1.P.Seq F M00064270B:B03 CR21PRN 15791 569532 RTA22200252F.h.18.1.P.Seq F M00063613D:C11 CH21PRN 15792 170313 RTA22200255F.g.20.1.P.Seq F M00063949D:A05 CH21PRN 15793 818682 RTA22200253F.p.14.1.P.Seq F M00063841A:B09 CH21PRN 15794 377188 RTA22200255F.l.06.1.P.Seq F M00064043D:C09 CH21PRN 15795 518848 RTA22200257F.j.22.3.P.Seq F M00064186C:B03 CH21PRN 15796 45592 RTA22200259F.l.08.1.P.Seq F M00063557D:C07 CH22PRC 15797 819273 RTA22200255F.n.19.1.P.Seq F M00064053C:G04 CH21PRN 15798 397284 RTA22200251F.a.06.1.P.Seq F M00063151D:B10 CH21PRN 15799 818326 RTA22200258F.e.14.1.P.Seq F M00064260C:E05 CR21PRN 15800 819037 RTA22200251F.c.15.1.P.Seq F M00063452A:F08 CH21PRN 15801 817417 RTA22200253F.m.14.1.P.Seq F M00063818C:A09 CH21PRN 15802 819640 RTA22200254F.i.11.1.P.Seq F M00063891A:F11 CH21PRN 15803 818771 RTA22200254F.i.19.1.P.Seq F M00063892B:G02 CR21PRN 15804 389627 RTA22200254F.k.10.1.P.Seq F M00063898A:A10 CH21PRN 15805 379067 RTA22200260F.e.20.1.P.Seq F M00063593A:D03 CH22PRC 15806 818544 RTA22200251F.f.02.1.P.Seq F M00063463D:B05 CH21PRN 15807 819440 RTA22200251F.j.22.1.P.Seq F M00063485A:E05 CH21PRN 15808 817417 RTA22200251F.k.10.1.P.Seq F M00063487C:C02 CH21PRN 15809 385307 RTA22200262F.k.11.1.P.Seq F M00064352C:H01 CH22PRC 15810 611440 RTA22200263F.d.24.2.P.Seq F M00064386B:C02 CH22PRC 15811 376056 RTA22200259F.e.16.1.P.Seq F M00063538D:B01 CH22PRC 15812 611440 RTA22200263F.d.24.1.P.Seq F M00064386B:C02 CH22PRC 15813 820061 RTA22200264F.f.09.1.P.Seq F M00064457D:C09 CH22PRC 15814 617825 RTA22200264F.p.06.1.P.Seq F M00064508A:B09 CH22PRC 15815 819440 RTA22200257F.h.17.1.P.Seq F M00064173B:E01 CH21PRN 15816 819145 RTA22200266F.m.08.1.P.Seq F M00064631C:H11 CH22PRC 15817 817653 RTA22200265F.p.07.1.P.Seq F M00064579A:C06 CH22PRC 15818 611440 RTA22200263F.e.01.1.P.Seq F M00064386B:C02 CH22PRC 15819 375958 RTA22200264F.j.22.1.P.Seq F M00064476D:C04 CH22PRC 15820 611440 RTA22200257F.a.20.1.P.Seq F M00064144D:A07 CH21PRN 15821 831049 RTA22200266F.o.13.1.P.Seq F M00064637B:F03 CH22PRC 15822 818162 RTA22200266F.g.18.1.P.Seq F M00064610D:H01 CH22PRC 15823 553200 RTA22200263F.p.02.1.P.Seq F M00064429D:B07 CH22PRC 15824 139677 RTA22200254F.o.07.1.P.Seq F M00063910D:A12 CH21PRN 15825 139677 RTA22200252F.c.11.1.P.Seq F M00063520D:E11 CH21PRN 15826 397284 RTA22200262F.i.22.2.P.Seq F M00064346C:B09 CH22PRC 15827 385810 RTA22200256F.m.04.2.P.Seq F M00064126C:F12 CH21PRN 15828 404624 RTA22200261F.e.07.1.P.Seq F M00063997C:B12 CH22PRC 15829 375958 RTA22200262F.b.14.2.P.Seq F M00064322C:A10 CH22PRC 15830 616555 RTA22200265F.b.24.1.P.Seq F M00064520A:E04 CH22PRC 15831 616555 RTA22200265F.c.01.1.P.Seq F M00064520A:E04 CH22PRC 15832 295694 RTA22200260F.o.20.1.P.Seq F M00063978B:B06 CH22PRC 15833 36113 RTA22200265F.e.06.1.P.Seq F M00064526D:F05 CH22PRC 15834 831812 RTA22200263F.f.05.1.P.Seq F M00064390A:C05 CH22PRC 15835 817653 RTA22200252F.g.23.1.P.Seq F M00063610D:C11 CH21PRN 15836 397284 RTA22200252F.m.15.1.P.Seq F M00063636A:E01 CH21PRN 15837 817979 RTA22200253F.p.15.1.P.Seq F M00063841A:E08 CH21PRN 15838 817653 RTA22200255F.m.18.1.P.Seq F M00064048C:G12 CH21PRN 15839 611440 RTA22200253F.f.03.1.P.Seq F M00063774A:D09 CH21PRN 15840 386014 RTA22200261F.f.06.1.P.Seq F M00064001A:B03 CH22PRC 15841 549981 RTA22200255F.b.10.1.P.Seq F M00063925B:F04 CH21PRN 15842 193373 RTA22200255F.l.21.1.P.Seq F M00064046A:G02 CH21PRN 15843 400619 RTA22200255F.g.14.1.P.Seq F M00063947D:D01 CH21PRN 15844 831149 RTA22200261F.o.21.1.P.Seq F M00064310D:F03 CH22PRC 15845 36113 RTA22200255F.d.16.1.P.Seq F M00063932D:G08 CH21PRN 15846 817503 RTA22200253F.l.16.1.P.Seq F M00063805D:E05 CH21PRN 15847 376588 RTA22200260F.i.11.1.P.Seq F M00063955D:F05 CH22PRC 15848 141079 RTA22200252F.f.23.1.P.Seq F M00063606C:B04 CH21PRN 15849 818063 RTA22200253F.p.04.1.P.Seq F M00063839A:F01 CH21PRN 15850 455264 RTA22200253F.n.14.1.P.Seq F M00063828A:H12 CH21PRN 15851 189234 RTA22200251F.f.17.1.P.Seq F M00063466C:C11 CH21PRN 15852 295694 RTA22200265F.j.05.1.P.Seq F M00064550A:A07 CH22PRC 15853 648679 RTA22200260F.f.06.1.P.Seq F M00063594B:H07 CH22PRC 15854 830930 RTA22200264F.e.10.1.P.Seq F M00064452D:E11 CH22PRC 15855 818497 RTA22200256F.d.07.1.P.Seq F M00064079C:A10 CH21PRN 15856 373928 RTA22200256F.d.19.1.P.Seq F M00064082A:A08 CH21PRN 15857 385307 RTA22200263F.j.12.1.P.Seq F M00064406B:H06 CH22PRC 15858 403453 RTA22200266F.e.10.1.P.Seq F M00064601D:B05 CH22PRC 15859 730318 RTA22200264F.c.09.1.P.Seq F M00064447B:A07 CH22PRC 15860 44183 RTA22200271F.a.01.1.P.Seq F M00021929A:D03 CH03MAH 15861 373928 RTA22200255F.d.22.1.P.Seq F M00063934B:E04 CH21PRN 15862 404624 RTA22200255F.d.23.1.P.Seq F M00063934C:C10 CH21PRN 15863 403173 RTA22200253F.a.21.1.P.Seq F M00063685A:C02 CH21PRN 15864 372700 RTA22200253F.c.06.1.P.Seq F M00063689D:E12 CH21PRN 15865 374343 RTA22200261F.h.04.1.P.Seq F M00064008A:B01 CH22PRC 15866 597854 RTA22200255F.j.03.1.P.Seq F M00064033D:B01 CH21PRN 15867 817417 RTA22200255F.a.23.1.P.Seq F M00063922B:A12 CH21PRN 15868 818497 RTA22200257F.k.05.3.P.Seq F M00064188B:G08 CH21PRN 15869 377696 RTA22200255F.f.15.1.P.Seq F M00063943B:G12 CH21PRN 15870 379105 RTA22200252F.n.19.1.P.Seq F M00063642B:A08 CH21PRN 15871 831188 RTA22200267F.o.02.1.P.Seq F M00064723D:H11 CH22PRC 15872 376056 RTA22200253F.m.09.1.P.Seq F M00063810C:E03 CH21PRN 15873 124863 RTA22200255F.n.15.1.P.Seq F M00064053B:D09 CH21PRN 15874 376056 RTA22200254F.i.03.1.P.Seq F M00063890A:F11 CH21PRN 15875 831812 RTA22200266F.j.10.1.P.Seq F M00064620C:D01 CH22PRC 15876 141079 RTA22200260F.i.14.1.P.Seq F M00063956A:F05 CH22PRC 15877 19148 RTA22200265F.o.18.1.P.Seq F M00064577C:B12 CH22PRC 15878 124396 RTA22200252F.a.14.1.P.Seq F M00063514C:E08 CH21PRN 15879 831026 RTA22200265F.c.03.1.P.Seq F M00064520A:F08 CH22PRC 15880 819037 RTA22200263F.i.23.1.P.Seq F M00064405B:C04 CH22PRC 15881 380207 RTA22200263F.i.19.1.P.Seq F M00064404C:G05 CH22PRC 15882 819460 RTA22200255F.c.13.1.P.Seq F M00063928A:G09 CH21PRN 15883 379067 RTA22200253F.g.23.1.P.Seq F M00063784C:E10 CH21PRN 15884 403173 RTA22200252F.p.23.1.P.Seq F M00063682A:C04 CH21PRN 15885 3856 RTA22200269F.a.05.1.P.Seq F M00003773D:H02 CH01COH 15886 378551 RTA22200263F.d.17.1.P.Seq F M00064385D:C11 CH22PRC 15887 456089 RTA22200272F.a.09.1.P.Seq F M00043134A:A05 CH19COP 15888 549981 RTA22200267F.a.22.1.P.Seq F M00064650B:B07 CH22PRC 15889 378551 RTA22200265F.m.21.1.P.Seq F M00064568A:H06 CH22PRC 15890 819201 RTA22200256F.n.23.2.P.Seq F M00064132B:B07 CH21PRN 15891 374826 RTA22200251F.c.20.1.P.Seq F M00063453B:F08 CH21PRN 15892 389409 RTA22200253F.l.23.1.P.Seq F M00063807A:D12 CH21PRN 15893 819149 RTA22200260F.a.17.1.P.Seq F M00063575B:G02 CH22PRC 15894 389409 RTA22200255F.e.18.1.P.Seq F M00063939C:D06 CH21PRN 15895 818165 RTA22200254F.h.15.1.P.Seq F M00063888D:F02 CH21PRN 15896 817757 RTA22200252F.i.15.1.P.Seq F M00063617D:F09 CH21PRN 15897 553242 RTA22200263F.i.20.1.P.Seq F M00064404D:A06 CH22PRC 15898 385615 RTA22200265F.b.08.1.P.Seq F M00064517B:F10 CH22PRC 15899 819102 RTA22200258F.h.19.1.P.Seq F M00064272C:G01 CH21PRN 15900 817757 RTA22200255F.o.16.1.P.Seq F M00064057C:H10 CH21PRN 15901 385615 RTA22200265F.b.07.1.P.Seq F M00064517B:F04 CH22PRC 15902 385615 RTA22200253F.l.06.1.P.Seq F M00063804C:A11 CH21PRN 15903 827355 RTA22200266F.n.23.1.P.Seq F M00064636B:A04 CH22PRC 15904 817629 RTA22200259F.a.13.1.P.Seq F M00063165A:C09 CH22PRC 15905 817514 RTA22200260F.h.02.1.P.Seq F M00063600C:C09 CH22PRC 15906 817514 RTA22200252F.p.21.1.P.Seq F M00063681B:C02 CH21PRN 15907 680563 RTA22200265F.f.13.1.P.Seq F M00064530B:H02 CH22PRC 15908 827355 RTA22200255F.e.20.1.P.Seq F M00063939C:H01 CH21PRN 15909 377286 RTA22200254F.a.04.1.P.Seq F M00063843B:D07 CH21PRN 15910 680563 RTA22200258F.g.18.1.P.Seq F M00064268D:G03 CH21PRN 15911 819156 RTA22200255F.h.06.1.P.Seq F M00064021D:H01 CH21PRN 15912 220584 RTA22200261F.f.22.1.P.Seq F M00064003B:C10 CH22PRC 15913 616555 RTA22200263F.o.12.1.P.Seq F M00064428B:A12 CH22PRC 15914 819498 RTA22200254F.o.14.1.P.Seq F M00063912A:D06 CH21PRN 15915 817508 RTA22200257F.h.01.1.P.Seq F M00064171D:E05 CH21PRN 15916 817690 RTA22200257F.e.05.1.P.Seq F M00064159A:H03 CH21PRN 15917 819156 RTA22200256F.h.13.1.P.Seq F M00064106C:G03 CH21PRN 15918 830904 RTA22200266F.j.12.1.P.Seq F M00064620D:G05 CH22PRC 15919 819498 RTA22200253F.b.04.1.P.Seq F M00063686B:E07 CH21PRN 15920 817508 RTA22200257F.g.24.1.P.Seq F M00064171D:E05 CH21PRN 15921 817508 RTA22200252F.a.19.1.P.Seq F M00063515B:F06 CH21PRN 15922 831160 RTA22200267F.h.01.1.P.Seq F M00064690A:C04 CH22PRC 15923 817762 RTA22200252F.k.13.1.P.Seq F M00063627C:F06 CH21PRN 15924 377286 RTA22200266F.k.07.1.P.Seq F M00064624C:B03 CH22PRC 15925 831160 RTA22200267F.g.24.1.P.Seq F M00064690A:C04 CH22PRC 15926 819994 RTA22200256F.k.11.1.P.Seq F M00064119C:D12 CH21PRN 15927 819994 RTA22200256F.k.09.1.P.Seq F M00064119B:H10 CH21PRN 15928 373298 RTA22200259F.c.19.1.P.Seq F M00063533A:C12 CH22PRC 15929 819894 RTA22200256F.m.03.2.P.Seq F M00064126C:C02 CH21PRN 15930 372718 RTA22200260F.b.22.1.P.Seq F M00063580D:B06 CH22PRC 15931 827355 RTA22200262F.l.20.1.P.Seq F M00064358A:G03 CH22PRC 15932 819894 RTA22200255F.d.09.1.P.Seq F M00063931B:E10 CH21PRN 15933 827355 RTA22200266F.e.07.1.P.Seq F M00064601C:G07 CH22PRC 15934 372718 RTA22200256F.l.03.1.P.Seq F M00064122C:B06 CH21PRN 15935 647435 RTA22200251F.b.10.1.P.Seq F M00063156D:H10 CH21PRN 15936 450262 RTA22200265F.a.10.1.P.Seq F M00064514A:G10 CH22PRC 15937 484703 RTA22200255F.i.20.1.P.Seq F M00064032D:G04 CH21PRN 15938 819498 RTA22200256F.f.12.1.P.Seq F M00064089B:F09 CH21PRN 15939 406043 RTA22200263F.i.12.1.P.Seq F M00064404A:B05 CH22PRC 15940 817500 RTA22200255F.f.24.1.P.Seq F M00063945A:C03 CH21PRN 15941 818180 RTA22200264F.o.18.1.P.Seq F M00064506A:C07 CH22PRC 15942 818143 RTA22200251F.a.03.1.P.Seq F M00063151A:G06 CH21PRN 15943 819756 RTA22200267F.a.18.1.P.Seq F M00064649A:E04 CH22PRC 15944 406908 RTA22200257F.i.18.3.P.Seq F M00064176D:H10 CH21PRN 15945 124863 RTA22200256F.o.21.2.P.Seq F M00064136C:D12 CH21PRN 15946 429009 RTA22200257F.e.24.1.P.Seq F M00064161B:G04 CH21PRN 15947 402586 RTA22200257F.i.24.3.P.Seq F M00064178B:A05 CH21PRN 15948 400475 RTA22200254F.i.04.1.P.Seq F M00063890A:H04 CH21PRN 15949 403453 RTA22200264F.d.12.1.P.Seq F M00064450C:E07 CH22PRC 15950 383021 RTA22200259F.d.06.1.P.Seq F M00063534C:A02 CH22PRC 15951 394913 RTA22200254F.p.10.1.P.Seq F M00063915C:E01 CH21PRN 15952 831361 RTA22200263F.k.19.1.P.Seq F M00064414D:D06 CH22PRC 15953 646020 RTA22200267F.n.21.1.P.Seq F M00064723C:H04 CH22PRC 15954 831361 RTA22200263F.l.03.1.P.Seq F M00064415B:G03 CH22PRC 15955 831580 RTA22200261F.f.18.1.P.Seq F M00064002C:H09 CH22PRC 15956 402586 RTA22200257F.j.01.3.P.Seq F M00064178B:A05 CH21PRN 15957 400475 RTA22200262F.j.21.1.P.Seq F M00064349D:H01 CH22PRC 15958 818937 RTA22200262F.h.14.2.P.Seq F M00064341A:C02 CH22PRC 15959 557697 RTA22200261F.j.20.1.P.Seq F M00064018C:E07 CH22PRC 15960 831361 RTA22200265F.m.24.1.P.Seq F M00064569B:A09 CH22PRC 15961 194490 RTA22200252F.c.10.1.P.Seq F M00063520D:D08 CH21PRN 15962 818143 RTA22200254F.b.18.1.P.Seq F M00063848C:G11 CH21PRN 15963 377286 RTA22200259F.a.10.1.P.Seq F M00063163A:G04 CH22PRC 15964 831361 RTA22200265F.n.01.1.P.Seq F M00064569B:A09 CH22PRC 15965 385307 RTA22200255F.p.07.1.P.Seq F M00064060B:D03 CH21PRN 15966 378447 RTA22200251F.c.01.1.P.Seq F M00063158A:E11 CH21PRN 15967 378447 RTA22200251F.b.24.1.P.Seq F M00063158A:E11 CH21PRN 15968 817514 RTA22200260F.m.17.1.P.Seq F M00063968D:G08 CH22PRC 15969 818942 RTA22200255F.f.03.1.P.Seq F M00063941B:C12 CH21PRN 15970 818942 RTA22200267F.e.23.1.P.Seq F M00064678D:F05 CH22PRC 15971 817363 RTA22200266F.f.04.1.P.Seq F M00064605C:G05 CH22PRC 15972 818942 RTA22200255F.i.02.1.P.Seq F M00064025D:E07 CH21PRN 15973 818942 RTA22200265F.g.23.1.P.Seq F M00064534D:F06 CH22PRC 15974 817457 RTA22200267F.e.15.1.P.Seq F M00064675C:E09 CH22PRC 15975 831968 RTA22200263F.f.23.1.P.Seq F M00064393B:H04 CH22PRC 15976 530941 RTA22200253F.h.05.1.P.Seq F M00063785C:F03 CH21PRN 15977 763446 RTA22200257F.j.05.3.P.Seq F M00064179A:C04 CH21PRN 15978 763446 RTA22200255F.n.21.1.P.Seq F M00064053D:F02 CH21PRN 15979 819219 RTA22200256F.f.16.1.P.Seq F M00064090C:A02 CH21PRN 15980 763446 RTA22200258F.b.19.2.P.Seq F M00064248A:E02 CH21PRN 15981 10154 15982 10154

TABLE 121 Nearest Nearest Neighbor Neighbor (BlastX vs. Non- (BlastN vs. Redundant SEQ Genbank) Proteins) ID ACCESSION DESCRIPTION P VALUE ACCESSION DESCRIPTION P VALUE 15685 <NONE> <NONE> <NONE> 1077580 hypothetical 7 protein YDR125c - yeast 15686 <NONE> <NONE> <NONE> 4585925 (AC007211) 6 unknown protein 15687 <NONE> <NONE> <NONE> 1085306 EVI1 protein - 4.3 human 15688 <NONE> <NONE> <NONE> 3876587 (Z81521) 0.85 predicted using Genefinder; cDNA EST yk233g4.5 comes from this gene; cDNA EST yk233g4.3 comes from this gene [Caenorhabditis elegans] 15689 <NONE> <NONE> <NONE> 1086591 (U41007) 0.34 similar to S. cervisiae nuclear protein SNF2 15690 <NONE> <NONE> <NONE> 157272 (L11345) DNA- 0.29 binding protein [Drosophila melanogaster] 15691 <NONE> <NONE> <NONE> 2633160 (Z99108) 0.19 similar to surface adhesion YfiQ [Bacillus subtilis] 15692 <NONE> <NONE> <NONE> 755468 (U19879) 0.042 transmembrane protein [Xenopus laevis] 15693 <NONE> <NONE> <NONE> 4507339 T brachyury 0.029 (mouse) homolog protein [Homo sapiens] 15694 <NONE> <NONE> <NONE> 729711 PROTEASE 0.004 DEGS PRECURSOR 3.4.21.—) hhoB - Escherichia coli >gi|558913 (U15661) HhoB [Escherichia coli] >gi|606174 (U18997) ORF_o355 coli] >gi|1789630 (AE000402) protease [Escherichia coli] 15695 <NONE> <NONE> <NONE> 3168911 (AF068718) No 8e−013 definition line found [Caenorhabditis elegans] 15696 <NONE> <NONE> <NONE> 2832777 (AL021086)/ 3e−040 prediction = (method:; comes from the 5′ UTR [Drosophila melanogaster] 15697 X78712 H. sapiens 2.1 2852449 (D88207) 9.1 mRNA for protein kinase glycerol kinase [Arabidopsis testis specific 2 thaliana] >gi|2947061 (AC002521) putative protein kinase 15698 X60760 L. esculentum 2.1 157272 (L11345) DNA- 5 TDR8 mRNA binding protein [Drosophila melanogaster] 15699 U40853 Oryctolagus 2 <NONE> <NONE> <NONE> cuniculus pulmonary surfactant protein B (SP-B) gene, complete cds 15700 AF083655 Homo sapiens 2 <NONE> <NONE> <NONE> procollagen C- proteinase enhancer protein (PCOLCE) gene, 5′ flanking region and complete cds 15701 AJ223776 Staphylococcus 2 <NONE> <NONE> <NONE> warneri hld gene 15702 U40853 Oryctolagus 2 <NONE> <NONE> <NONE> cuniculus pulmonary surfactant protein B (SP-B) gene, complete cds 15703 X04436 Clostridium 2 <NONE> <NONE> <NONE> tetani gene for tetanus toxin 15704 Z35787 S. cerevisiae 2 157272 (L11345) DNA- 8.4 chromosome II binding protein reading frame [Drosophila ORF YBL026w melanogaster] 15705 X78712 H. sapiens 2 2852449 (D88207) 8.2 mRNA for protein kinase glycerol kinase [Arabidopsis testis specific 2 thaliana] >gi|2947061 (AC002521) putative protein kinase 15706 Z15056 B. subtilis genes 2 477124 P3A2 DNA 2.8 spoVD, murE, binding protein mraY, murD homolog EWG - fruit fly (Drosophila melanogaster) 15707 S65623 cAMP-regulated 2 119266 PROTEIN 0.55 enhancer- GRAINY- binding protein HEAD (DNA- 1 of 3] BINDING PROTEIN ELF- 1) (ELEMENT I-BINDING ACTIVITY) regulatory protein elf-1 - fruit fly (Drosophila melanogaster) >gi|7939|emb |CAA33692| (X15657) Elf-1 protein (AA 1- 1063) [Drosophila melanogaster] 15708 NM_004415.1 Homo sapiens 2 2649177 (AE001008) 0.2 desmoplakin conserved (DPI, DPII) hypothetical (DSP) mRNA protein mRNA, [Archaeoglobus complete cds fulgidus] 15709 AF031552 Vibrio cholerae 2 2088714 (AF003139) 2e−013 magnesium strong similarity transporter to NADPH (mgtE) gene, oxidases; partial partial cds; CDS, the gene sensor kinase begins in the (vieS), response neighboring regulator clone (vieA), and response regulator (vieB) genes, complete cds; and collagenase (vcc) gene, partial cds 15710 AF116852.1 Danio rerio 2 3800951 (AF100657) No 2e−019 dickkopf-1 definition line (dkk1) mRNA, found complete cds [Caenorhabditis elegans] 15711 X82595 P. sativum fuc 1.9 <NONE> <NONE> <NONE> gene 15712 AF008216 Homo sapiens 1.9 <NONE> <NONE> <NONE> candidate tumor suppressor pp32r1 15713 AF130672.1 Felis catus clone 1.9 <NONE> <NONE> <NONE> Fca603 microsatellite sequence 15714 AJ007044 Oryctolagus 1.9 388055 (L22981) 7.8 Cuniculus sod merozoite gene surface protein- 1 [Plasmodium chabaudi] 15715 AC004497 Homo sapiens 1.9 160925 (M94346) 7.7 chromosome 21, A.1.12/9 P1 clone antigen LBNL#6 [Schistosoma mansoni] 15716 U30290 Rattus 1.9 3024079 GALECTIN-4 4.5 norvegicus (LACTOSE- galanin receptor BINDING GALR1 mRNA, LECTIN 4) (L- complete cds 36 LACTOSE BINDING PROTEIN) (L36LBP) >gi|2281707 sapiens] >gi|2623387 (U82953) galectin-4 [Homo sapiens] 15717 Y13234 Chironomus 1.9 4567068 (AF125568) 3.4 tentans mRNA tumor for chitinase, suppressing STF 1695 bp cDNA 4 [Homo sapiens] 15718 NM_003644.1 Homo sapiens 1.9 125560 PROTEIN 0.53 growth arrest- KINASE C, specific 7 GAMMA TYPE (GAS7) mRNA C (EC 2.7.1.—) > :: gamma - rabbit emb|AJ224876| >gi|165652 HSAJ4876 (M19338) Homo sapience protein kinase mRNA for delta GAS7 protein [Oryctolagus cuniculus] 15719 AB013448.1 Oryza sativa 1.8 <NONE> <NONE> <NONE> gene for Pib, complete cds 15720 D63854 Human 1.8 <NONE> <NONE> <NONE> cytomegalovirus DNA, replication origin 15721 AB002340 Human mRNA 1.8 <NONE> <NONE> <NONE> for KIAA0342 gene, complete cds 15722 AF017779 Mus musculus 1.8 <NONE> <NONE> <NONE> vitamin D receptor gene, promoter region 15723 D63854 Human 1.8 <NONE> <NONE> <NONE> cytomegalovirus DNA, replication origin 15724 M24102 Bovine 1.8 <NONE> <NONE> <NONE> ADP/ATP translocase T1 mRNA, complete cds. 15725 AC004497 Homo sapiens 1.8 <NONE> <NONE> <NONE> chromosome 21, P1 clone LBNL#6 15726 M37394 Rat epidermal 1.8 <NONE> <NONE> <NONE> growth factor receptor mRNA. 15727 AF006304 Saccharomyces 1.8 <NONE> <NONE> <NONE> cerevisiae protein tyrosine phosphatase (PTP3) gene, complete cds 15728 D13454 Candida 1.8 <NONE> <NONE> <NONE> albicans CACHS3 gene for chitin synthase III 15729 Y00354 Xenopus laevis 1.8 1077580 hypothetical 7.5 gene encoding protein vitellogenin A2 YDR125c - yeast 15730 U90936 Aspergillus 1.8 4337033 (AF124138) 7.3 niger px27 transcriptional gene, promoter activator protein region CdaR [Streptomyces coelicolor] transcriptional regulator [Streptomyces coelicolor] 15731 D84448 Cavia cobaya 1.8 4704603 (AF109916) 7.1 mRNA for putative Na+, K+- dehydrin ATPase beta-3 subunit, complete cds 15732 AF039948 Xenopus laevis 1.8 1695839 (U58151) 5.6 clone H-0 envelope transcription glycoprotein elongation factor [Human S-II (TFIIS) immunodeficiency precursor RNA, virus type 1] isoform TFIIS.h, partial cds 15733 M18061 Xenopus laevis 1.8 780502 (U18466) AP 3.1 vitelloginin endonuclease gene, complete class II [African cds. swine fever virus] >gi|10975251|prf ||2113434ET AP endonuclease: ISO TYPE = class II [African swine fever virus] 15734 U61112 Mus musculus 1.8 3043646 (AB011133) 1.9 Eya3 homolog KIAA0561 mRNA, protein [Homo complete cds sapiens] 15735 AB018442 Oryza sativa 1.8 4455041 (AF116463) 0.49 mRNA for unknown phytochrome C, [Streptomyces complete cds lincolnensis] 15736 D63854 Human 1.8 1169200 DNA- 0.22 cytomegalovirus DAMAGE- DNA, replication REPAIR/TOLERATION origin PROTEIN DRT111 PRECURSOR >gi|421829|pir ||S33706 DNA-damage resistance protein - Arabidopsis thaliana and DNA-damage resistance protein (DRT111) mRNA, complete cds.], gene product [Arabidopsis thaliana] 15737 D26549 Bovine mRNA 1.8 755468 (U19879) 0.042 for adseverin, transmembrane complete cds protein [Xenopus laevis] 15738 J05211 Human 1.8 728867 ANTER- 0.015 desmoplakin SPECIFIC mRNA, 3′ end. PROLINE- RICH PROTEIN APG PRECURSOR >gi|99694|pir ||S21961 proline-rich protein APG - Arabidopsis thaliana >gi|22599|emb |CAA42925| 15739 NM_004415.1 Homo sapiens 1.8 728867 ANTER- 0.015 desmoplakin SPECIFIC (DPI, DPII) PROLINE- (DSP) mRNA RICH mRNA, PROTEIN APG complete cds PRECURSOR >gi|99694|pir ||S21961 proline-rich protein APG - Arabidopsis thaliana >gi|22599|emb |CAA42925| 15740 AF038604 Caenorhabditis 1.8 3877951 (Z81555) 3e−008 elegans cosmid predicted using B0546 Genefinder 15741 AF038604 Caenorhabditis 1.8 3877951 (Z81555) 2e−011 elegans cosmid predicted using B0546 Genefinder 15742 U23551 Prochlorothrix 1.8 2828280 (AL021687) 2e−013 hollandica putative protein phosphomannomutase [Arabidopsis thaliana] >gi|2832633|emb |CAA16762 |(AL021711) putative protein [Arabidopsis thaliana] 15743 S60150 ORF1. . . ORF6 1.8 1065454 (U40410) 2e−019 {3′ terminal C54G7.2 gene reigon} product [chrysanthemum [Caenorhabditis virus B CVB, elegans] Genomic RNA, 6 genes, 3426 nt] 15744 AB014558 Homo sapiens 1.8 3850072 (AL033385) 6e−027 mRNA for dna-directed rna KIAA0658 polymerase iii protein, partial subunit cds [Schizosaccharo myces pombe] 15745 X17191 E. gracilis 1.7 <NONE> <NONE> <NONE> chloroplast RNA polymerase rpoB-rpoC1- rpoC2 operon 15746 X07729 R. norvegicus 1.7 4584544 (AL049608) 8.8 gene encoding extensin-like neuron-specific protein enolase, exons 8–12 15747 D38178 Human gene for 1.7 73714 infected cell 1.1 cytosolic protein ICP34.5 - phospholipase human A2, exon 1 herpesvirus 1 (strain F) >gi|330123 (M12240) infected cell protein [Herpes simplex virus type 1] 15748 U23551 Prochlorothrix 1.7 2828280 (AL021687) 2e−010 hollandica putative protein phosphomannomutase [Arabidopsis thaliana] >gi|2832633|emb |CAA16762 |(AL021711) putative protein [Arabidopsis thaliana] 15749 Y00525 Klebsiella 1.6 3800951 (AF100657) No 6e−013 pneumoniae definition line nifL gene for found regulatory [Caenorhabditis protein elegans] 15750 AF100170.1 Bos taurus 1.5 463552 (U05877) AF-1 0.074 major fibrous [Homo sapiens] sheath protein precursor, mRNA, complete cds 15751 Y13441 Homo sapiens 0.74 <NONE> <NONE> <NONE> Rox gene, exon 2 15752 L46792 Actinidia 0.73 3170252 (AF043636) 0.001 deliciosa clone circumsporozoite AdXET-5 protein xyloglucan [Plasmodium endotransglycosylase chabaudi] precursor (XET) mRNA, complete cds 15753 U73489 Drosophila 0.7 3915994 HYPOTHETICAL 3e−005 melanogaster 53.2 KD Nem (nem) PROTEIN IN mRNA, PRC-PRPA complete cds INTERGENIC REGION 15754 U95097 Xenopus laevis 0.68 157272 (L11345) DNA- 8.5 mitotic binding protein phosphoprotein [Drosophila 43 mRNA, melanogaster] partial cds 15755 AF082012 Caenorhabditis 0.67 2494313 PUTATIVE 8.4 elegans UDP-N- TRANSLATION acetylglucosamine: INITIATION a-3-D- FACTOR EIF- mannoside b- 2B SUBUNIT 1 1,2-N- (EIF-2B GDP- acetylglucosaminyltransferase I GTP (gly-14) mRNA, EXCHANGE complete cds FACTOR) eIF- 2B, subunit alpha- Methanococcus jannaschii aIF- 2B, subunit delta (aIF2BD) [Methanococcus jannaschii] 15756 U04354 Mus musculus 0.67 4755188 (AC007018) 8e−026 ADSEVERIN unknown protein mRNA, complete cds 15757 M68881 S. pombe cigl+ 0.67 2078441 (U56964) weak 2e−030 gene, complete similarity to S. cerevisiae cds. intracellular protein transport protein US)1 (SP: P25386) 15758 U95097 Xenopus laevis 0.66 2829685 PROTEIN- 6.2 mitotic TYROSINE phosphoprotein PHOSPHATASE X 43 mRNA, PRECURSOR partial cds (R-PTP-X) (PTP IA- 2BETA) (PROTEIN TYROSINE PHOSPHATASE- NP) (PTP- NP) >gi|1515425 (U57345) protein tyrosine phosphatase-NP [Mus musculus] 15759 Z15056 B. subtilis genes 0.66 477124 P3A2 DNA 2.1 spoVD, murE, binding protein mraY, murD homolog EWG - fruit fly (Drosophila melanogaster) 15760 M86808 Human pyruvate 0.65 <NONE> <NONE> <NONE> dehydrogenase complex (PDHA2) gene, complete cds. 15761 J03754 Rat plasma 0.65 4507549 transmembrane 8e−006 membrane protein with Ca2+ ATPase- EGF-like and isoform 2 two follistatin- mRNA, like domains 1 complete cds. >gi|755466 15762 NM_000887.1 Homo sapiens 0.64 <NONE> <NONE> <NONE> integrin, alpha X (antigen CD11C emb|Y00093|HSP15095 H. sapiens mRNA for leukocyte adhesion glycoprotein p150, 95 15763 L27080 Human 0.64 <NONE> <NONE> <NONE> melanocortin 5 receptor (MC5R) gene, complete cds. 15764 U07890 Mus musculus 0.64 <NONE> <NONE> <NONE> C57BL/6J epidermal surface antigen (mesa) mRNA, complete cds. 15765 AF079139 Streptomyces 0.64 3041869 (U96109) 2.8 venezuelae proline-rich pikCD operon, transcription complete factor ALX3 sequence [Mus musculus] 15766 M16140 Chicken 0.64 123984 ACROSIN 4e−008 ovoinhibitor INHIBITORS gene, exon 15. IIA AND IIB 15767 NM_000887.1 Homo sapiens 0.63 <NONE> <NONE> <NONE> integrin, alpha X (antigen CD11C emb|Y00093|HSP15095 H. sapiens mRNA for leukocyte adhesion glycoprotein p150, 95 15768 Z17316 Kluyveromyces 0.63 <NONE> <NONE> <NONE> lactis for gene encoding phosphofructokinase beta subunit 15769 Z25470 H. sapiens 0.63 <NONE> <NONE> <NONE> melanocortin 5 receptor gene, complete CDS 15770 L19954 Bacillus subtilis 0.63 <NONE> <NONE> <NONE> feuA, B, and C genes, 3 ORFs, 2 complete cds's and 5'end. 15771 U44405 Spiroplasma 0.63 2499642 SERINE/THREONINE- 7.7 citri PROTEIN chromosome KINASE STE20 pre-inversion HOMOLOG border, SPV1- >gi|1737181 like sequences, (U73457) transposase Cst20p [Candida gene, partial albicans] cds, adhesin-like protein P58 gene, complete cds. 15772 Z28264 S. cerevisiae 0.63 3880930 (AL021481) 2e−014 chromosome XI similar to reading frame Phosphoglucomutase ORF YKR039w and phosphomannomutase phosphoserine; cDNA EST EMBL: D36168 comes from this gene; cDNA EST EMBL: D70697 comes from this gene; cDNA EST yk373h9.5 comes from this gene; cDNA EST EMBL: T00805 . . . 15773 AE001107 Archaeoglobus 0.62 <NONE> <NONE> <NONE> fulgidus section 172 of 172 of the complete genome 15774 Z14112 B. firmus TopA 0.62 310115 (L02530) 0.026 gene encoding Drosophila DNA polarity gene topoisomerase I (frizzled) homologue 15775 AF118101 Toxoplasma 0.62 726403 (U23175) 4e−018 gondii protein similar to anion kinase 6 (tpk6) exchange mRNA, protein complete cds [Caenorhabditis elegans] 15776 M59743 Rabbit cardiac 0.61 <NONE> <NONE> <NONE> muscle Ca-2+ release channel 15777 M12036 Human tyrosine 0.61 61962 (X58484) gag 7.5 kinase-type [Simian foamy receptor (HER2) virus] gene, partial cds. 15778 AF043195 Homo sapiens 0.61 1572629 (U69699) 7.5 tight junction unknown protein protein ZO (ZO- precursor [Mus 2) gene, musculus] alternative splice products, promoter and exon A 15779 U18178 Human HLA 0.61 1336688 (S81116) 5.7 class I genomic properdin survey [guinea pigs, sequence. spleen, Peptide, 470 aa] [Cavia] 15780 U44405 Spiroplasma 0.61 2827531 (AL021633) 3.3 citri hypothetical chromosome protein pre-inversion border, SPV1- like sequences, transposase gene, partial cds, adhesin-like protein P58 gene, complete cds. 15781 Z33011 M. capricolum 0.61 3915729 HYPERPLASTIC 0.26 DNA for DISCS CONTIG PROTEIN MC008 (HYD PROTEIN) >gi|2673887 (L14644) hyperplastic discs protein 15782 NM_001429.1 Homo sapiens 0.61 4204294 (AC003027) 5e−005 E1A binding lcl|prt_seq No protein p300 definition line mRNA, found complete cds. > :: gb|I62297|I62297 Sequence 1 from patent US 5658784 15783 Z25418 C. familiaris 0.61 3877493 (Z48583) 1e−007 MHC class Ib similar to gene (DLA-79) ATPases gene, complete associated with CDS various cellular activities (AAA); cDNA EST EMBL: Z14623 comes from this gene; cDNA EST EMBL: D75090 comes from this gene; cDNA EST EMBL: D72255 comes from this gene; cDNA EST yk200e4.5 . . . 15784 AB002150 Bacillus subtilis 0.6 <NONE> <NONE> <NONE> DNA for FeuB, FeuA, YbbB, YbbC, YbbD, YbzA, YbbE, YbbF, YbbH, YbbI, YbbJ, YbbK, YbbL, YbbM, YbbP, complete cds 15785 Y07786 V. cholerae 0.6 <NONE> <NONE> <NONE> ORF's involved in lipopolysaccharide synthese 15786 Z17316 Kluyveromyces 0.6 <NONE> <NONE> <NONE> lactis for gene encoding phosphofructokinase beta subunit 15787 Z71403 S. cerevisiae 0.6 <NONE> <NONE> <NONE> chromosome XIV reading frame ORF YNL127w 15788 L34641 Homo sapiens 0.6 1147634 (U42213) 9.6 platelet/endothelial micronemal cell adhesion TRAP-C1 molecule-1 protein homolog (PECAM-1) gene, exon 10. 15789 AF070572 Homo sapiens 0.6 399034 N- 2.5 clone 24778 ACETYLMUR unknown AMOYL-L- mRNA ALANINE AMIDASE AMIB PRECURSOR >gi|628763|pir ||S41741 N- acetylmuramoyl- L-alanine amidase (EC 3.5.1.28) - Escherichia coli >gi|304914 (L19346) N- acetylmuramoyl- L-alanine amidase [Escherichia coli] N- acetylmuramoyl- l-alanine amidase II; a 15790 X75627 C. burnetii trxB, 0.6 3036833 (AJ003163) 0.28 spoIIIE and serS apsB genes [Emericella nidulans] 15791 Z99765 Flaveria pringleigdcsH 0.59 <NONE> <NONE> <NONE> gene 15792 U02538 Mycoplasma 0.59 <NONE> <NONE> <NONE> hyopneumoniae J ATCC 25934 23S rRNA gene, partial sequence 15793 Z71403 S. cerevisiae 0.59 <NONE> <NONE> <NONE> chromosome XIV reading frame ORF YNL127w 15794 X03942 Mouse simple 0.59 <NONE> <NONE> <NONE> repetitive DNA (sqr family) transcript (clone pmlc 2) with conserved GACA/GATA repeats 15795 U11844 Mus musculus 0.59 <NONE> <NONE> <NONE> glucose transporter (GLUT3) gene, exon 1 15796 D63395 Homo sapiens 0.59 4433616 (AF107018) 1.8 mRNA for alpha- NOTCH4, mannosidase IIx partial cds [Mus musculus] 15797 Z33011 M. capricolum 0.59 3915729 HYPERPLASTIC 0.27 DNA for DISCS CONTIG PROTEIN MC008 (HYD PROTEIN) >gi|2673887 (L14644) hyperplastic discs protein 15798 U05670 Haemophilus 0.58 <NONE> <NONE> <NONE> influenzae DL42 Lex2A and Lex2B genes, complete cds. 15799 L27080 Human 0.58 123984 ACROSIN 2e−006 melanocortin 5 INHIBITORS receptor IIA AND IIB (MC5R) gene, complete cds. 15800 AF043195 Homo sapiens 0.57 1572629 (U69699) 6.7 tight junction unknown protein protein ZO (ZO- precursor [Mus 2) gene, musculus] alternative splice products, promoter and exon A 15801 U57707 Bos taurus 0.57 807646 (M17294) 0.068 activin receptor unknown protein type IIB [Human precursor herpesvirus 4] 15802 Z17316 Kluyveromyces 0.56 <NONE> <NONE> <NONE> lactis for gene encoding phosphofructokinase beta subunit 15803 M21535 Human erg 0.56 <NONE> <NONE> <NONE> protein (ets- related gene) mRNA, complete cds. 15804 M64932 Candida maltosa 0.56 3219524 (AF069428) 1.3 cyclohexamide NADH resistance dehydrogenase protein subunit IV [Alligator mississippiensis] >gi|3367630|e mb|CAA73570| (Y13113) NADH dehydrogenase subunit 4 [Alligator mississippiensis] 15805 AE000342 Escherichia coli 0.56 3874685 (Z78539) 0.088 K-12 MG1655 Similarity to section 232 of S. pombe 400 of the hypothetical complete protein genome C4G8.04 (SW: YAD4_SC HPO); cDNA EST EMBL: D27846 comes from this gene; cDNA EST EMBL: D27845 comes from this gene; cDNA EST yk202h7.3 comes from this gene; cDNA EST yk202h7.5 come . . . 15806 Z15056 B. subtilis genes 0.55 477124 P3A2 DNA 3.7 spoVD, murE, binding protein mraY, murD homolog EWG - fruit fly (Drosophila melanogaster) 15807 Z58167 H. sapiens CpG 0.53 <NONE> <NONE> <NONE> island DNA genomic Mse1 fragment, clone 30e10, forward read cpg30e10.ft1b 15808 M27159 Rat potassium 0.53 1850920 (U21247) Bet 0.9 channel-Kv2 [Human gene, partial spumaretrovirus] cds. 15809 M15555 Mouse Ig 0.24 <NONE> <NONE> <NONE> germline V- kappa-24 chain (VK24C) gene, exons 1 and 2. 15810 U95097 Xenopus laevis 0.24 399109 TRANSCRIPTION 4 mitotic FACTOR phosphoprotein BF-1 (BRAIN 43 mRNA, FACTOR 1) partial cds (BF1) >gi|92020|pir ||JH0672 brain factor 1 protein - rat >gi|203135 (M87634) BF-1 [Rattus norvegicus] 15811 AJ002014 Crythecodinium 0.24 416704 BALBIANI 0.36 cohnii mRNA RING for nuclear PROTEIN 3 protein JUS1 PRECURSOR balbiani ring 3 (BR3) [Chironomus tentans] 15812 L35330 Rattus 0.23 1388158 (U58204) 8.8 norvegicus myomesin glutathione S- [Gallus gallus] transferase Yb3 subunit gene, complete cds. 15813 NM_001432.1 Homo sapiens 0.23 2851520 TRANSFORMING 2e−008 epiregulin GROWTH (EREG) mRNA FACTOR > :: ALPHA dbj|D30783|D3 PRECURSOR 0783 Homo (TGF-ALPHA) sapiens mRNA (EGF-LIKE for epiregulin, TGF) (ETGF) complete cds (TGF TYPE 1) precursor - rat >gi|207282 (M31076) transforming growth factor alpha precursor [Rattus norvegicus] 15814 U57043 Cebus apella 0.22 <NONE> <NONE> <NONE> gamma globin (gamma 1) gene, complete cds 15815 AB023188.1 Homo sapiens 0.22 <NONE> <NONE> <NONE> mRNA for KIAA0971 protein, complete cds 15816 M18105 Yeast 0.22 <NONE> <NONE> <NONE> (S. cerevisiae) SST2 gene encoding desensitization to alpha- factor pheromone, complete cds. 15817 AJ001113 Homo sapiens 0.22 3122961 ENHANCER 8.5 UBE3A gene, OF SPLIT exon 16 GROUCHO- LIKE PROTEIN 1 >gi|2408145 (U18775) enhancer of split groucho 15818 L35330 Rattus 0.22 1388158 (U58204) 8.1 norvegicus myomesin glutathione S- [Gallus gallus] transferase Yb3 subunit gene, complete cds. 15819 D42042 Human mRNA 0.22 4827063 zinc finger 6.1 for KIAA0085 protein 142 gene, partial cds (clone pHZ-49) >gi|3123312|s p|P52746|Z142_(—) HUMAN ZINC FINGER PROTEIN 142 (KIAA0236) (HA4654) >gi|1510147|d bj|BAA13242| 15820 L35330 Rattus 0.22 2853301 (AF007194) 1.6 norvegicus mucin [Homo glutathione S- sapiens] transferase Yb3 subunit gene, complete cds. 15821 Z11653 H. sapiens DBH 0.22 3819705 (AL032824) 1.2 gene complex syntaxin binding repeat protein 1; sec1 polymorphism family secretory DNA. protein [Schizosaccharo myces pombe] 15822 L29063 Candida 0.22 3046871 (AB003753) 0.32 albicans fatty high sulfur acid synthase protein B2E alpha subunit [Rattus (FAS2) gene, norvegicus] complete cds. 15823 M64865 Horse alcohol 0.22 2213909 (AF004874) 0.037 dehydrogenase- latent TGF-beta S-isoenzyme binding protein- mRNA, 2 [Mus complete cds. musculus] 15824 Y09472 B. taurus gene 0.21 2909874 (AF047829) 7.6 encoding melatonin- preprododecape related receptor ptide [Ovis aries] 15825 Y09472 B. taurus gene 0.21 2909874 (AF047829) 7.5 encoding melatonin- preprododecape related receptor ptide [Ovis aries] 15826 X80301 N. tabacum axi 1 0.21 2832715 (AJ003066) 6 gene subunit beta of the mitochondrial fatty acid beta- oxydation multienzyme complex [Bos taurus] 15827 AF073485 Homo sapiens 0.21 2224559 (AB002307) 3.3 MHC class I- KIAA0309 related protein [Homo sapiens] MR1 precursor (MR1) gene, partial cds 15828 S78251 growth hormone 0.21 729381 DYNAMIN-1 2 receptor (DYNAMIN {alternatively BREDNM19) spliced, exon 1B} [sheep, Merino, skeletal muscle, mRNA Partial, 438 nt] 15829 U16135 Synechococcus 0.21 135514 T-CELL 0.02 sp. Clp protease RECEPTOR proteolytic BETA CHAIN subunit PRECURSOR precursor (ANA 11) - rabbit 15830 X95601 M. hominis lmp3 0.21 2995445 (Y10496) CDV- 0.005 and lmp4 genes 1 protein [Mus musculus] 15831 X95601 M. hominis lmp3 0.21 2995447 (Y10495) CDV- 0.005 and lmp4 genes 1R protein [Mus musculus] 15832 AF124249.1 Homo sapiens 0.21 423456 epidermal 8e−010 SH2-containing growth factor- protein Nsp1 receptor-binding mRNA, protein GRB-4 - complete cds mouse (fragment) 15833 AF030282 Danio rerio 0.21 3928083 (AC005770) 2e−014 homeobox unknown protein protein Six7 [Arabidopsis (six7) mRNA, thaliana] complete cds 15834 X83427 O. anatinus 0.21 132575 RIBONUCLEASE 3e−021 mitochondrial INHIBITOR DNA, complete genome 15835 AJ001113 Homo sapiens 0.2 <NONE> <NONE> <NONE> UBE3A gene, exon 16 15836 AF081533.1 Anopheles 0.2 <NONE> <NONE> <NONE> gambiae putative gram negative bacteria binding protein gene, complete cds 15837 U70316 Dictyostelium 0.2 <NONE> <NONE> <NONE> discoideum IonA (iona) gene, partial cds 15838 AF009341 Homo sapiens 0.2 <NONE> <NONE> <NONE> E6-AP ubiquitin-protein ligase 15839 L35330 Rattus 0.2 3702275 (AC005793) 2.5 norvegicus KIAA0561 glutathione S- protein [AA 1–593] transferase Yb3 [Homo subunit gene, sapiens] complete cds. 15840 AE000573.1 Helicobacter 0.2 3947855 (AL034381) 2.5 pylori 26695 putative Golgi section 51 of membrane 134 of the protein complete genome 15841 X83230 G. gallus 0.2 3258596 (U95821) 0.81 hsp90beta gene putative transmembrane GTPase [Drosophila melanogaster] 15842 X57157 Chicken mRNA 0.2 108325 insulin-like 0.17 for Hsp47, heat growth factor- shock protein 47 binding protein 6 15843 M58748 Chicken alpha- 0.2 1086863 (U41272) 4e−005 globin gene T03G11.6 gene domain with product structural matrix [Caenorhabditis attachment sites. elegans] 15844 AB016815 Anthocidaris 0.2 423456 epidermal 1e−012 crassispina growth factor- mRNA for Src- receptor-binding type protein protein GRB-4 - tyrosine kinase, mouse complete cds (fragment) 15845 AF030282 Danio rerio 0.2 3928083 (AC005770) 3e−014 homeobox unknown protein protein Six7 [Arabidopsis (six7) mRNA, thaliana] complete cds 15846 AL035559 Streptomyces 0.2 2088714 (AF003139) 3e−022 coelicolor strong similarity cosmid 9F2 to NADPH oxidases; partial CDS, the gene begins in the neighboring clone 15847 S79641 SDH = succinate 0.2 4755188 (AC007018) 2e−022 dehydrogenase unknown protein flavoprotein subunit Mutant, 387 nt] 15848 X75383 H. sapiens 0.19 <NONE> <NONE> <NONE> mRNA for TFIIA-alpha 15849 U53901 Hippopotamus 0.19 <NONE> <NONE> <NONE> amphibius b- casein gene, exon 7, partial cds 15850 J05265 Mouse 0.19 77356 hypothetical 0.0005 interferon 70K protein - gamma receptor eggplant mosaic mRNA, virus complete cds. 15851 U72353 Rattus 0.19 3880857 (AL031633) 2e−006 norvegicus cDNA EST lamin B1 yk404d1.5 mRNA, comes from this complete cds gene; cDNA EST yk404d1.3 comes from this gene 15852 AB016815 Anthocidaris 0.19 3930217 (AF047487) 2e−007 crassispina Nck-2 [Homo mRNA for Src- sapiens] type protein tyrosine kinase, complete cds 15853 D10911 Mus musculus 0.19 2662366 (D86332) 5e−011 DNA for MS2 membrane type- protein, 2 matrix complete cds metalloproteinase [Mus musculus] 15854 AB015345 Homo sapiens 0.075 3877417 (Z66564) 6.4 HRIHFB2216 similar to anion mRNA, partial exchange cds protein 15855 AF086410 Homo sapiens 0.075 3023371 PHEROMONE 4.9 full length insert B BETA 1 cDNA clone RECEPTOR ZD77B03 15856 K02024 Human T-cell 0.075 2791527 (AL021246) 0.11 lymphotropic PE_PGRS virue type II env [Mycobacterium gene encoding tuberculosis] envelope glycoprotein, complete cds. 15857 M10188 X. laevis 0.074 4753163 huntingtin 2.8 mitochondrial DISEASE DNA containing PROTEIN) (HD the D-loop, and PROTEIN) the 12S rRNA, >gi|454415 apocytochrome (L12392) b, Glu-tRNA, Huntington's Thr-tRNA, Pro- Disease protein tRNA and Phe- [Homo sapiens] tRNA genes. 15858 X85525 G. gallus AG 0.073 984339 (U20966) Rev 3.6 repeat region [Simian (GgaMU130) immunodeficiency virus] 15859 AJ238394.1 Homo sapiens 0.07 4240219 (AB020672) 2 AML2 gene KIAA0865 (partial) protein [Homo sapiens] 15860 AF039704 Homo sapiens 0.069 2894106 (Z78279) 0.39 lysosomal Collagen alpha1 pepstatin [Rattus insensitive norvegicus] protease (CLN2) gene, complete cds 15861 K02024 Human T-cell 0.068 4504857 potassium 0.5 lymphotropic intermediate/small virue type II env conductance gene encoding calcium- envelope activated glycoprotein, channel, complete cds. subfamily N, member 3 >gi|3309531 (AF031815) calcium- activated potassium channel [Homo sapiens] 15862 Z60719 H. sapiens CpG 0.068 4826874 nucleoporin 0.044 island DNA 214 kD (CAIN) genomic Mse1 PROTEIN fragment, clone NUP214 33a11, forward (NUCLEOPORIN read NUP214) cpg33a11.ft1m (214 KD NUCLEOPORIN) transforming protein (can) - human sapiens] 15863 AF053994 Lycopersicon 0.068 2842699 PUTATIVE 9e−009 esculentum UBIQUITIN Hcr2-0A (Hcr2- CARBOXYL- 0A) gene, TERMINAL complete cds HYDROLASE C6G9.08 (UBIQUITIN THIOLESTERASE) (UBIQUITIN- SPECIFIC PROCESSING PROTEASE) 15864 AJ233650.1 Equus caballus 0.067 <NONE> <NONE> <NONE> endogenous retroviral sequence ERV- L pol gene, clone ERV-L Horse1 15865 M10188 X. laevis 0.067 4753163 huntingtin 2.5 mitochondrial DISEASE DNA containing PROTEIN) (HD the D-loop, and PROTEIN) the 12S rRNA, >gi|454415 apocytochrome (L12392) b, Glu-tRNA, Huntington's Thr-tRNA, Pro- Disease protein tRNA and Phe- [Homo sapiens] tRNA genes. 15866 U14646 Murine hepatitis 0.067 3880930 (AL021481) 1e−019 virus Y strain S similar to glycoprotein Phosphoglucomutase gene, complete and cds. phosphomannomutase phosphoserine; cDNA EST EMBL: D36168 comes from this gene; cDNA EST EMBL: D70697 comes from this gene; cDNA EST yk373h9.5 comes from this gene; cDNA EST EMBL: T00805 . . . 15867 X15373 Mouse 0.066 164507 (M81771) 9.4 cerebellum immunoglobulin mRNA for P400 gamma-chain protein [Sus scrofa] 15868 AF086410 Homo sapiens 0.066 3023371 PHEROMONE 4.2 full length insert B BETA 1 cDNA clone RECEPTOR ZD77B03 15869 AL034492 Streptomyces 0.066 3800951 (AF100657) No 3e−015 coelicolor definition line cosmid 6C5 found [Caenorhabditis elegans] 15870 L13377 Staphylococcus 0.065 <NONE> <NONE> <NONE> aureus enterotoxin gene, 3′ end. 15871 U83478 Thelephoraceae 0.065 3877335 (Z92786) 9.1 sp. ‘Taylor #13’ predicted using ITS1, 5.8S Genefinder ribosomal RNA gene, and ITS2, complete sequence 15872 AJ002014 Crythecodinium 0.065 1213283 (U40576) SIM2 0.47 cohnii mRNA [Mus musculus] for nuclear protein JUS1 15873 AB016804 Aloe 0.065 2832777 (AL021086)/ 5e−036 arborescens prediction = (method:; mRNA for comes NADP-malic from the 5′ enzyme, UTR complete cds [Drosophila melanogaster] 15874 AJ002014 Crythecodinium 0.063 1213283 (U40576) SIM2 0.45 cohnii mRNA [Mus musculus] for nuclear protein JUS1 15875 AB023143.1 Homo sapiens 0.024 132575 RIBONUCLEASE 8e−026 mRNA for INHIBITOR KIAA0926 protein, complete cds 15876 U72966 Human 0.022 <NONE> <NONE> <NONE> hepatocyte nuclear factor 4- alpha gene, exon 7 15877 X02801 Mouse gene for 0.022 2231607 (U85917) nef 7 glial fibrillary protein [Human acidic protein immunodeficiency virus type 1] 15878 AF017636 Mesocricetus 0.022 2723362 (AF023459) 0.097 auratus 3-keto- lustrin A steroid reductase [Haliotis rufescens] 15879 Z36879 F. pringlei 0.008 <NONE> <NONE> <NONE> gdcsPA gene for P-protein of the glycine cleavage system 15880 X73150 P. sativum 0.008 1572629 (U69699) 8.6 GapC1 gene unknown protein precursor [Mus musculus] 15881 AJ239031.1 Homo sapiens 0.008 4508019 zinc finger 0.01 LSS gene, protein 231 partial, exons protein [Homo 22, 23 and sapiens] joined CDS 15882 U76602 Human 180 kDa 0.007 3170252 (AF043636) 0.0001 bullous circumsporozoite pemphigoid protein antigen 2/type [Plasmodium XVII collagen chabaudi] (BPAG2/COL17A1) gene, exons 49, 50, 51 and 52 15883 M11283 Aplysia 0.007 3874685 (Z78539) 9e−013 californica Similarity to FMRFamide S. pombe mRNA, partial hypothetical cds, clone protein FMRF-2. C4G8.04 (SW: YAD4_SCHPO); cDNA EST EMBL: D27846 comes from this gene; cDNA EST EMBL: D27845 comes from this gene; cDNA EST yk202h7.3 comes from this gene; cDNA EST yk202h7.5 come . . . 15884 J03998 P. falciparum 0.003 <NONE> <NONE> <NONE> glutamic acid- rich protein gnen, complete cds. 15885 Z23143 M. musculus 0.002 2393890 (AF006064) 1e−011 ALK-6 mRNA, protein kinase complete CDS homolog [Fowlpox virus] 15886 AB007914 Homo sapiens 0.001 2136964 cysteine-rich 1.9 mRNA for hair keratin KIAA0445 associated protein, protein - rabbit complete cds >gi|510541|emb |CAA56339| (X80035) cysteine rich hair keratin associated protein 15887 AB012105 Brassica rapa 0.0008 3687246 (AC005169) 5.5 mRNA for putative SLG45, suppressor complete cds protein [Arabidopsis thaliana] 15888 L41608 Methylobacterium 0.0008 3024235 NERVOUS- 5.1 extorquens SYSTEM (clone pDN9, SPECIFIC HINDIIIAB) OCTAMER- mxaS gene 3′ BINDING end, mxaA, TRANSCRIPTION mxaC, mxaK, FACTOR mxaL and mxaD N-OCT 3 genes, complete PROTEIN) cds. 15889 AB007914 Homo sapiens 0.0008 2136964 cysteine-rich 2.5 mRNA for hair keratin KIAA0445 associated protein, protein - rabbit complete cds >gi|510541|emb |CAA56339| (X80035) cysteine rich hair keratin associated protein 15890 AC002293 Genomic 0.0008 2789557 (AF034316) 0.0002 sequence from MHC class I Human 9q34, antigen [Triakis complete scyllium] sequence [Homo scyllium] sapiens] 15891 L16013 Rattus 9e−005 <NONE> <NONE> <NONE> norvegicus Q- like gene sequence 15892 AF148512.1 Homo sapiens 9e−005 <NONE> <NONE> <NONE> hexokinase II gene, promoter region 15893 U94776 Human muscle 9e−005 4759138 solute carrier 5.4 glycogen family 7 phosphorylase transporter 3 (PYGM) gene, [Homo sapiens] exons 6 through 17 15894 X56030 H. sapiens IAPP 1e−005 <NONE> <NONE> <NONE> gene for amyloid polypeptide, exon 1 15895 U36515 Human CT 4e−007 2435616 (AF026215) No 0.85 microsatellite, definition line clone GM5927- found CT-2-3, from [Caenorhabditis the tandemly elegans] repeated genes encoding U2 small nuclear RNA (RNU2 locus) 15896 AB011119 Homo sapiens 4e−007 4758508 airway trypsin- 3e−031 mRNA for like protease KIAA0547 protease [Homo protein, sapiens] complete cds 15897 NM_000521.1 Homo sapiens 5e−008 2119379 slow muscle 2.8 hexosaminidase troponin T - B (beta chicken T polypeptide) [Gallus gallus] (HEXB) mRNA 15898 X13895 Human serum 4e−008 699405 (U18682) novel 7.7 amyloid A antigen receptor (GSAA1) gene, [Ginglymostoma complete cds cirratum] 15899 AB009288.1 Homo sapiens 4e−008 4520342 (AB008893) N- 3e−006 mRNA for N- copine [Mus copine, musculus] complete cds 15900 AB011119 Homo sapiens 4e−008 4758508 airway trypsin- 1e−028 mRNA for like protease KIAA0547 protease [Homo protein, sapiens] complete cds 15901 X13895 Human serum 5e−009 699405 (U18682) novel 7.8 amyloid A antigen receptor (GSAA1) gene, [Ginglymostoma complete cds cirratum] 15902 X13895 Human serum 2e−009 699405 (U18682) novel 7.2 amyloid A antigen receptor (GSAA1) gene, [Ginglymostoma complete cds cirratum] 15903 U64997 Bos taurus 2e−009 3914810 RIBONUCLEASE 3e−018 ribonuclease K6 K6 gene, partial cds PRECURSOR (RNASE K6) >gi|2745760 (AF037086) ribonuclease k6 precursor 15904 J02635 Rat liver alpha- 2e−009 112913 ALPHA-2- 4e−019 2-macroglobulin MACROGLOBULIN mRNA, PRECURSOR complete cds. precursor - rat >gi|202592 (J02635) prealpha-2- macroglobulin [Rattus norvegicus] 15905 Z78141 M. musculus 5e−010 3219569 (AL023893)/ 4e−009 partial cochlear prediction = (method:; mRNA (clone 29C9) 15906 AF060917 Gambusia 2e−010 3874618 (Z48241) 0.096 affinis similar to coiled microsatellite coil domains; Gafu6 cDNA EST yk302g12.5 comes from this gene; cDNA EST yk365d10.5 comes from this gene; cDNA EST yk461c1.5 comes from this gene [Caenorhabditis elegans] coil domains; cDNA EST yk302g12.5 comes from this gene; cDNA EST 15907 U68138 Human PSD-95 2e−010 4521241 (AB024927) 2e−022 mRNA, partial CsENDO-3 cds [Ciona savignyi] 15908 U88827 Aotus trivirgatus 6e−011 3914810 RIBONUCLEASE 1e−016 ribonuclease K6 precursor gene, PRECURSOR complete cds (RNASE K6) >gi|2745760 (AF037086) ribonuclease k6 precursor 15909 AF045573 Mus musculus 2e−012 3025718 (AF045573) 3e−016 FLI-LRR FLI-LRR associated associated protein-1 protein-1 [Mus mRNA, musculus] complete cds 15910 NM_001365.1 Homo sapiens 2e−012 4521241 (AB024927) 5e−020 discs, large CsENDO-3 (Drosophila) [Ciona savignyil] homolog 4 (DLG4) mRNA > :: gb|U83192|HS U83192 Homo sapiens post- synaptic density protein 95 (PSD95) mRNA, complete cds 15911 U28049 Human TBX2 7e−013 2501115 TBX2 2e−011 (TXB2) mRNA, PROTEIN (T- complete cds. BOX PROTEIN 2) 15912 M23404 Chicken 2e−013 726403 (U23175) 1e−025 erythrocyte similar to anion anion transport exchange protein (band3) protein mRNA, [Caenorhabditis complete cds. elegans] 15913 AF005963 Homo sapiens 1e−014 104270 Ig heavy chain - 1.9 XY homologous clawed frog region, partial sequence 15914 M29863 Human farnesyl 9e−015 182405 (M29863) 0.005 pyrophosphate farnesyl synthetase pyrophosphate mRNA synthetase [Homo sapiens] 15915 D28126 Human gene for 3e−015 <NONE> <NONE> <NONE> ATP synthase alpha subunit, complete cds (exon 1 to 12) 15916 Z80150 H. sapiens 3e−015 3387914 (AF070550) 3.5 CACNL1A4 cote1 [Homo gene, exons 41 sapiens] and 42 > :: emb|A70716.1| A70716 Sequence 37 from Patent WO9813490 15917 U28049 Human TBX2 4e−016 2501116 TBX2 6e−009 (TXB2) mRNA, PROTEIN (T- complete cds. BOX PROTEIN 2) tbx gene [Mus musculus] 15918 U31629 Mus musculus 1e−017 3024998 HYPOTHETICAL 3e−017 C2C12 unknown HEART mRNA, partial PROTEIN cds. 15919 J05262 Human farnesyl 1e−018 182405 (M29863) 0.0001 pyrophosphate farnesyl synthetase pyrophosphate mRNA, synthetase complete cds. [Homo sapiens] 15920 D28126 Human gene for 5e−019 <NONE> <NONE> <NONE> ATP synthase alpha subunit, complete cds (exon 1 to 12) 15921 D28126 Human gene for 5e−019 3219984 HYPOTHETICAL 5.7 ATP synthase PROTEIN alpha subunit, MJ1597.1 complete cds region (exon 1 to 12) MJ1597.1 [Methanococcus jannaschii] 15922 NM_004587.1 Homo sapiens 2e−019 4759056 ribosome 0.004 ribosome binding protein binding protein 1 (dog 180 kD 1 (dog 180 kD homolog) homolog) >gi|3299885 (RRBP1) (AF006751) mRNA > :: ES/130 [Homo gb|AF006751| sapiens] AF006751 Homo sapiens ES/130 mRNA, complete cds 15923 U89915 Mus musculus 5e−020 3462455 (U89915) 2e−005 junctional junctional adhesion adhesion molecule (Jam) molecule [Mus mRNA, musculus] complete cds 15924 AF045573 Mus musculus 5e−020 3025718 (AF045573) 9e−025 FLI-LRR FLI-LRR associated associated protein-1 protein-1 [Mus mRNA, musculus] complete cds 15925 NM_004587.1 Homo sapiens 2e−020 4759056 ribosome 0.0008 ribosome binding protein binding protein 1 (dog 180 kD 1 (dog 180 kD homolog) homolog) >gi|3299885 (RRBP1) (AF006751) mRNA > :: ES/130 [Homo gb|AF006751| sapiens] AF006751 Homo sapiens ES/130 mRNA, complete cds 15926 AF051098 Mus musculus 2e−021 3858883 (U67056) 0.002 seven myosin I heavy transmembrane chain kinase domain orphan [Acanthamoeba receptor mRNA, castellanii] complete cds >gi|4206769 (AF104910) myosin I heavy chain kinase [Acanthamoeba castellanii] 15927 AF051098 Mus musculus 2e−021 3858883 (U67056) 0.001 seven myosin I heavy transmembrane chain kinase domain orphan [Acanthamoeba receptor mRNA, castellanii] complete cds >gi|4206769 (AF104910) myosin I heavy chain kinase [Acanthamoeba castellanii] 15928 M13519 Human N- 2e−021 4504373 hexosaminidase 2e−007 acetyl-beta- B (beta glucosaminidase polypeptide) (HEXB) >gi|123081|sp mRNA, 3′ end. |P07686|HEXB_(—) HUMAN BETA- HEXOSAMINIDASE BETA CHAIN PRECURSOR beta-N- acetylhexosaminidase (EC 3.2.1.52) beta chain - human >gi|386770 (M23294) beta- hexosaminidase beta-subunit [Homo sapiens] 15929 Z81014 Human DNA 2e−022 <NONE> <NONE> <NONE> sequence from cosmid U65A4, between markers DXS366 and DXS87 on chromosome X* 15930 AF147311.1 Homo sapiens 2e−022 3875904 (Z70207) 0.07 full length insert predicted using cDNA clone Genefinder; YA82F10 similar to collagen; cDNA EST EMBL: D65905 comes from this gene; cDNA EST EMBL: D65858 comes from this gene; cDNA EST EMBL: D69306 comes from this gene; cDNA EST EMBL: D65755 comes from this gen... 15931 AF037088 Gorilla gorilla 9e−024 3914791 RIBONUCLEASE 3e−019 ribonuclease k6 K6 precursor, gene, PRECURSOR complete cds (RNASE K6) >gi|2745752 (AF037082) ribonuclease k6 precursor 15932 Z81014 Human DNA 8e−024 <NONE> <NONE> <NONE> sequence from cosmid U65A4, between markers DXS366 and DXS87 on chromosome X* 15933 AF037088 Gorilla gorilla 9e−025 3914810 RIBONUCLEASE 4e−018 ribonuclease k6 K6 precursor, gene, PRECURSOR complete cds (RNASE K6) >gi|2745760 (AF037086) ribonuclease k6 precursor 15934 AF147311.1 Homo sapiens 1e−026 131413 PULMONARY 0.059 full length insert SURFACTANT- cDNA clone ASSOCIATED YA82F10 PROTEIN A PRECURSOR (SP-A) (PSP-A) (PSAP) precursor - rabbit >gi|165706 (J03542) apoprotein of surfactant [Oryctolagus cuniculus] 15935 Z46786 D. melanogaster 1e−027 1079042 acetyl-CoA 4e−025 mRNA for synthetase - fruit acetyl-CoA fly synthetase 15936 NM_004039.1 Homo sapiens 4e−028 450448 (M33322) 0.1 annexin II calpactin I (lipocortin II) heavy chain for lipocortin II, [Mus musculus] complete cds 15937 X53064 Homo sapiens 1e−028 134846 SMALL 0.005 SPRR2A gene PROLINE- encoding small RICH proline rich PROTEIN II protein rich protein [Homo sapiens] 15938 M29863 Human farnesyl 1e−028 4503685 farnesyl 2e−008 pyrophosphate diphosphate synthetase synthase mRNA dimethylallyltranstransferase, geranyltranstransferase) bp313 to bp1374 is almost identical to human farnesyl pyrophosphate synthetase mRNA. [Homo sapiens] 15939 Z18950 H. sapiens genes 5e−029 2493898 DOPAMINE- 1.4 for S100E BETA- calcium binding MONOOXYGE protein, CAPL, NASE and S100D PRECURSOR calcium binding (DOPAMINE protein EF- BETA- Hand patent US HYDROXYLASE) 5789248 (DBH) 1.14.17.1) precursor - mouse >gi|260873|bbs |119249 621 aa] [Mus sp.] 15940 M19481 Human 5e−030 <NONE> <NONE> <NONE> follistatin gene, exon 6. 15941 AF007155 Homo sapiens 2e−032 4502641 chemokine (C- 1.6 clone 23763 C) receptor 7 unknown TYPE 7 mRNA, partial PRECURSOR cds (C-C CKR-7) (CC-CKR-7) (CCR-7) (MIP-3 BETA RECEPTOR) (EBV- INDUCED G PROTEIN- COUPLED RECEPTOR 1) (EBI1) (BLR2) >gi|1082381|Pir ∥B55735 lymphocyte- specific G- protein-coupled receptor EBI1 - human >gi|468316 (L3158 15942 M99624 Human 8e−034 294845 (L13655) 9e−014 epidermal membrane growth factor protein receptor-related [Saccharum gene, 5′ end. hybrid cultivar H65-7052] 15943 U49082 Human 8e−035 1840045 (U49082) 1e−014 transporter transporter protein (g17) protein [Homo mRNA, sapiens] complete cds 15944 D50369 Homo sapiens 9e−036 3024781 UBIQUINOL- 0.0002 mRNA for low CYTOCHROME C molecular mass REDUCTASE ubiquinone- COMPLEX binding protein, UBIQUINONE- complete cds BINDING PROTEIN QP- C PROTEIN) (COMPLEX III SUBUNIT VII) ubiquinone- binding protein [Homo sapiens] 15945 AF086313 Homo sapiens 9e−036 2832777 (AL021086)/ 1e−039 full length insert prediction = cDNA clone (method:; comes ZD52B10 from the 5′ UTR [Drosophila melanogaster] 15946 NM_004074.1 Homo sapiens 1e−038 2499854 PROBABLE 2 cytochrome c PEPTIDASE oxidase subunit Y4SO VIII (COX8), >gi|2182630 nuclear gene encoding mitochondrial protein, mRNA > :: gb|J04823|HU MCOX8A Human cytochrome c oxidase subunit VIII (COX8) mRNA, complete cds. 15947 AB024436.1 Homo sapiens 2e−041 3132900 (AF038662) 4e−016 mRNA for beta- beta-1,4- 1,4- galactosyltransferase galactosyltransferase [Homo IV, sapiens] beta- complete cds 1,4- galactosyltransferase IV [Homo sapiens] 15948 AF057734 Homo sapiens 2e−043 2842416 (AL008730) 3e−062 17-beta- dJ487J7.1.1 hydroxysteroid (putative protein dehydrogenase dJ487J7.1 IV (HSD17B4) isoform 1) gene, exon 16 [Homo sapiens] 15949 Z69650.1 Human DNA 2e−044 1872200 (U22376) 1e−008 sequence from alternatively cosmid L69F7B, spliced product Huntington's using exon 13A Disease Region, chromosome 4p16.3 contains Huntington Disease (HD) gene 15950 NM_003938.1 Homo sapiens 2e−044 3478639 (AC005545) 3e−016 adaptin, delta delta-adaptin, (ADTD) mRNA partial CDS > :: [Homo sapiens] gb|U91930|HS U91930 Homo sapiens AP-3 complex delta subunit mRNA, complete cds 15951 AF026029 Homo sapiens 8e−045 1916930 (U88570) 7.6 poly(A) binding CREB-binding protein II protein homolog (PABP2) gene, [Drosophila complete cds melanogaster] 15952 AB006622 Homo sapiens 1e−045 73404 E2 protein - 0.11 mRNA for human KIAA0284 papillomavirus gene, partial cds type 5 15953 U90918 Human clone 1e−048 3877568 (Z70208) 0.042 23654 mRNA similar to sequence collagen 15954 AB006622 Homo sapiens 1e−049 73404 E2 protein - 0.11 mRNA for human KIAA0284 papillomavirus gene, partial cds type 5 15955 AL049258.1 Homo sapiens 1e−050 <NONE> <NONE> <NONE> mRNA; cDNA DKFZp564E173 (from clone DKFZp564E173) 15956 AF022367 Homo sapiens 5e−051 3132900 (AF038662) 6e−019 beta-1,4- beta-1,4- galactosyltransferase galactosyltransferase mRNA, [Homo complete cds sapiens] beta- 1,4- galactosyltransferase IV [Homo sapiens] 15957 AF057734 Homo sapiens 7e−053 2842416 (AL008730) 6e−055 17-beta- dJ487J7.1.1 hydroxysteroid (putative protein dehydrogenase dJ487J7.1 IV (HSD17B4) isoform 1) gene, exon 16 [Homo sapiens] 15958 AF097709 Homo sapiens 8e−055 4506141 protease, serine, 2e−017 serine protease 11 (IGF (PRSS11) binding) mRNA, partial >gi|1513059|dbj cds |BAA13322| (D87258) serin protease with IGF-binding motif [Homo sapiens] protease, PRSS11 [Homo sapiens] 15959 U31629 Mus musculus 9e−057 3025215 HYPOTHETICAL 5e−033 C2C12 unknown 81.0 KD mRNA, partial PROTEIN cds. C35D10.4 IN CHROMOSOME III >gi|2146877|pir ∥S72572 probable ABC1 protein homolog - Caenorhabditis elegans protein (Swiss-Prot Acc: P27697) [Caenorhabditis elegans] 15960 AB006622 Homo sapiens 8e−057 73404 E2 protein - 1.7 mRNA for human KIAA0284 papillomavirus gene, partial cds type 5 15961 AF025439 Homo sapiens 4e−059 <NONE> <NONE> <NONE> Opa-interacting protein OIP3 mRNA, partial cds 15962 M99624 Human 1e−060 123364 SEGMENTATION 5.3 epidermal PROTEIN growth factor EVEN- receptor-related SKIPPED fly gene, 5′ end. (Drosophila sp.) >gi|157387 (M14767) even- skipped gene [Drosophila melanogaster] 15963 AF045573 Mus musculus 5e−061 3025718 (AF045573) 7e−029 FLI-LRR FLI-LRR associated associated protein-1 protein-1 [Mus mRNA, musculus] complete cds 15964 AB006622 Homo sapiens 2e−062 2119133 ribosomal 2e−015 mRNA for protein S17 - cat KIAA0284 (fragment) gene, partial cds musculus] 15965 M30702 Human 2e−063 4502199 amphiregulin 0.0002 amphiregulin (schwannoma- (AR) gene, exon derived growth 5, clones factor) lambda- >gi|113754|sp| ARH(6,12). P15514|AMP R_HUMAN AMPHIREGULIN PRECURSOR (AR) (COLORECTUM CELL- DERIVED GROWTH FACTOR) (CRDGF) >gi|107391|pir|| A34702 amphiregulin precursor - human >gi|178890 (M30703) amphiregulin [Homo sapien 15966 L38847 Mus musculus 6e−064 3861228 (AJ235272) 2.9 hepatoma unknown transmembrane [Rickettsia kinase ligand prowazekii] Sequence 1 from patent US 5624899 15967 L38847 Mus musculus 6e−064 3861228 (AJ235272) 2.9 hepatoma unknown transmembrane [Rickettsia kinase ligand prowazekii] Sequence 1 from patent US 5624899 15968 Z78141 M. musculus 8e−066 1490324 (Z78141) 8e−019 partial cochlear unknown [Mus mRNA (clone musculus] 29C9) 15969 X12650 Mus musculus 2e−072 833602 (X54277) 7e−022 gene for beta- cardiac tropomyosin tropomyosin [Coturnix coturnix] 15970 M87635 Mouse beta- 2e−084 1216293 (L35239) 5e−019 tropomyosin 2 cardiac mRNA, tropomyosin complete cds. [Xenopus laevis] 15971 M13364 Rabbit calcium- 2e−084 115611 CALCIUM- 1e−058 dependent DEPENDENT protease, small PROTEASE, subunit mRNA, SMALL complete cds. NEUTRAL PROTEINASE) (CANP) >gi|108563|pir|| A34466 calpain (EC 3.4.22.17) II light chain - bovine 3.4.22.17) [Bos taurus] 15972 M87635 Mouse beta- 3e−088 1216293 (L35239) 9e−028 tropomyosin 2 cardiac mRNA, tropomyosin complete cds. [Xenopus laevis] 15973 M87635 Mouse beta- 5e−092 1216293 (L35239) 2e−035 tropomyosin 2 cardiac mRNA, tropomyosin complete cds. [Xenopus laevis] 15974 X85992 M. musculus 8e−097 2137756 semaphorin C - 2e−048 mRNA for mouse semaphorin C (fragment) musculus] 15975 M24103 Bovine e−103 113463 ADP, ATP 2e−035 ADP/ATP CARRIER translocase T2 PROTEIN, mRNA, LIVER complete cds. ISOFORM T2 (ADP/ATP TRANSLOCASE 3) (ADENINE NUCLEOTIDE TRANSLOCATOR 3) (ANT 3) >gi|86757|pir|| S03894 ADP, ATP carrier protein T2 - human 15976 U48852 Cricetulus e−107 1216486 (U48852) HT 3e−057 griseus HT protein protein mRNA, [Cricetulus complete cds. griseus] 15977 X76168 R. norvegicus e−112 544118 GAP 1e−063 mRNA for JUNCTION connexin 30.3 BETA-5 PROTEIN (CONNEXIN 30.3) (CX30.3) >gi|481577|pir|| S38891 connexin 30.3 - rat >gi|431204|emb| CAA53762| (X76168) connexin 30.3 15978 X76168 R. norvegicus e−115 461864 GAP 7e−064 mRNA for JUNCTION connexin 30.3 BETA-5 PROTEIN junction protein Cx30.3 - mouse >gi|192647 (M91443) connexin 30.3 [Mus musculus] 15979 AJ009634.1 Mus musculus e−137 4138203 (AJ009634) 5e−065 fjx1 gene Fjx1 [Mus musculus] 15980 X76168 R. norvegicus e−130 544118 GAP 2e−074 mRNA for JUNCTION connexin 30.3 BETA-5 PROTEIN (CONNEXIN 30.3) (CX30.3) >gi|481577|pir|| S38891 connexin 30.3 - rat >gi|431204|emb| CAA53762| (X76168) connexin 30.3

Example 79 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including primary cells, cell lines and patient tissue samples. Table 122 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 122 Description of cDNA Libraries Number of Library Clones in (Lib#) Description Library 1 Human Colon Cell Line Km12 L4: High Metastatic 308731 Potential (derived from Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic Potential 284771 3 Human Breast Cancer Cell Line MDA-MB-231: High 326937 Metastatic Potential; micro-mets in lung 4 Human Breast Cancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung Cancer Cell Line MV-522: High Metastatic 223620 Potential 9 Human Lung Cancer Cell Line UCP-3: Low Metastatic 312503 Potential 12 Human microvascular endothelial cells (HMVEC) - 41938 UNTREATED (PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells (HMVEC) - bFGF 42100 TREATED (PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells (HMVEC) - 42825 VEGF TREATED (PCR (OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTED PCR 282722 (OligodT) cDNA library) 16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR 298831 (OligodT) cDNA library) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467 (MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED PCR 36216 (OligodT) cDNA library) 19 Colon Tumor - UC#3 Patient (MICRODISSECTED PCR 41388 (OligodT) cDNA library) 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 (MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived from normal prostate epithelium 164801 22 WOca Cells derived from Gleason Grade 4 prostate cancer 162088 epithelium 23- Normal Lung Epithelium of Patient #1006 306198 (MICRODISSECTED PCR (OligodT) cDNA library) 24 Primary tumor, Large Cell Carcinoma of Patient #1006 309349 (MICRODISSECTED PCR (OligodT) cDNA library)

The KM12L4 cell line is derived from the KM12C cell line (Morikawa, et al., Cancer Research (1988) 48:6863). The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246). The MDA-MB-231 cell line (Brinkley et al. Cancer Res. (1980) 40:3118-3129) was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma.

The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cells were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz cells were derived from normal prostate epithelium. The WOca cells are Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296-298 (1974).

Using this approach, a number of polynucleotide sequences were identified as being differentially expressed between, for example, cells derived from high metastatic potential cancer tissue and low metastatic cancer cells, and between cells derived from metastatic cancer tissue and normal tissue. Evaluation of the levels of expression of the genes corresponding to these sequences can be valuable in diagnosis, prognosis, and/or treatment (e.g., to facilitate rationale design of therapy, monitoring during and after therapy, etc.). Moreover, the genes corresponding to differentially expressed sequences described herein can be therapeutic targets due to their involvement in regulation (e.g., inhibition or promotion) of development of, for example, the metastatic phenotype. For example, sequences that correspond to genes that are increased in expression in high metastatic potential cells relative to normal or non-metastatic tumor cells may encode genes or regulatory sequences involved in processes such as angiogenesis, differentiation, cell replication, and metastasis.

Detection of the relative expression levels of differentially expressed polynucleotides described herein can provide valuable information to guide the clinician in the choice of therapy. For example, a patient sample exhibiting an expression level of one or more of these polynucleotides that corresponds to a gene that is increased in expression in metastatic or high metastatic potential cells may warrant more aggressive treatment for the patient. In contrast, detection of expression levels of a polynucleotide sequence that corresponds to expression levels associated with that of low metastatic potential cells may warrant a more positive prognosis than the gross pathology would suggest.

The differential expression of the polynucleotides described herein can thus be used as, for example, diagnostic markers, prognostic markers, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers.

The differential expression data for polynucleotides of the invention that have been identified as being differentially expressed across various combinations of the libraries described above is summarized in Table 123 (inserted prior to the claims). Table 123 provides: 1) the Sequence Identification Number (“SEQ ID”) assigned to the polynucleotide; 2) the cluster (“CLUST”) to which the polynucleotide has been assigned as described above; 3) the library comparisons that resulted in identification of the polynucleotide as being differentially expressed (“PairAB-text”), with shorthand names of the compared libraries provided in parentheses following the library numbers; 4) the number of clones corresponding to the polynucleotide in the first library listed (“A”); 5) the number of clones corresponding to the polynucleotide in the second library listed (“B”); 6) the “RATIO PLUS” where the comparison resulted in a finding that the number of clones in library A is greater than the number of clones in library B; and 7) the “RATIO MINUS” where the comparison resulted in a finding that the number of clones in library B is greater than the number of clones in library A.

TABLE 123 SEQ CLONES CLONES RATIO RATIO ID CLUST PairAB-text in A in B PLUS MINUS 15670 819498 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15674 728115 _15, 16 (Normal Colon vs. 0 7 6.62 Colon Tumor) _16, 17 (Colon Tumor vs. 7 0 7.11 Colon Metastasis) 15675 372700 _08, 09 (Lung, High Metastatic 3 50 11.93 Potential vs. Lung, Low Metastatic Potential) _19, 20 (Colon Tumor vs. 8 0 5.98 Colon Tumor Metastasis) 15678 729832 _15, 16 (Normal Colon vs. 0 11 10.41 Colon Tumor) _16, 17 (Colon Tumor vs. 11 0 11.17 Colon Metastasis) 15679 505514 _23, 24 (Normal Lung vs. Lung 26 10 2.63 Tumor) 15683 549934 _21, 22 (Normal Prostate vs. 8 0 7.87 Cancerous Prostate) _16, 17 (Colon Tumor vs. 3 20 6.56 Colon Metastasis) _15, 16 (Normal Colon vs. 11 3 3.88 Colon Tumor) 15691 450399 _15, 16 (Normal Colon vs. 28 68 2.3 Colon Tumor) _15, 17 (Normal Colon vs. 28 117 3.89 Colon Metastasis) 15692 450982 _16, 17 (Colon Tumor vs. 14 32 2.25 Colon Metastasis) 15694 379302 _21, 22 (Normal Prostate vs. 8 1 7.87 Cancerous Prostate) 15709 817503 _21, 22 (Normal Prostate vs. 18 4 4.43 Cancerous Prostate) 15714 830085 _21, 22 (Normal Prostate vs. 0 9 9.15 Cancerous Prostate) 15718 830931 _21, 22 (Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15721 819046 _21, 22 (Normal Prostate vs. 2 13 6.61 Cancerous Prostate) 15724 728115 _15, 16 (Normal Colon vs. 0 7 6.62 Colon Tumor) _16, 17 (Colon Tumor vs. 7 0 7.11 Colon Metastasis) 15731 553242 _16, 17 (Colon Tumor vs. 0 6 5.91 Colon Metastasis) 15737 820061 _21, 22 (Normal Prostate vs. 1 20 20.33 Cancerous Prostate) 15744 220584 _08, 09 (Lung, High Metastatic 1 12 8.59 Potential vs. Lung, Low Metastatic Potential) 15746 549934 _16, 17 (Colon Tumor vs. 3 20 6.56 Colon Metastasis) _15, 16 (Normal Colon vs. 11 3 3.88 Colon Tumor) _21, 22 (Normal Prostate vs. 8 0 7.87 Cancerous Prostate) 15752 819460 _21, 22 (Normal Prostate vs. 18 1 17.7 Cancerous Prostate) 15761 551785 _21, 22 (Normal Prostate vs. 0 6 6.1 Cancerous Prostate) 15762 17092 _03, 04 (Breast, High 0 25 25.62 Metastatic Potential vs. Breast, Non- Metastatic) 15765 745559 _21, 22 (Normal Prostate vs. 1 9 9.15 Cancerous Prostate) 15767 379879 _21, 22 (Normal Prostate vs. 0 9 9.15 Cancerous Prostate) 08, 09 (Lung, High Metastatic 0 13 9.3 Potential vs. Lung, Low Metastatic Potential) 15773 268290 _21, 22 (Normal Prostate vs. 33 69 2.13 Cancerous Prostate) 15774 818043 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15780 450247 _21, 22 (Normal Prostate vs. 23 8 2.83 Cancerous Prostate) 15781 819273 _21, 22 (Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15782 587779 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15784 615617 _21, 22 (Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15787 818682 _21, 22 (Normal Prostate vs. 11 2 5.41 Cancerous Prostate) 15789 484413 _21, 22 (Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15790 819273 _21, 22 (Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15793 818682 _21, 22 (Normal Prostate vs. 11 2 5.41 Cancerous Prostate) 15797 819273 _21, 22 (Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15813 820061 _21, 22 (Normal Prostate vs. 1 20 20.33 Cancerous Prostate) 15819 375958 _21, 22 (Normal Prostate vs. 2 11 5.59 Cancerous Prostate) _08, 09 (Lung, High Metastatic 0 9 6.44 Potential vs. Lung, Low Metastatic Potential) 15821 831049 _21, 22 (Normal Prostate vs. 0 11 11.18 Cancerous Prostate) 15823 553200 _21, 22 (Normal Prostate vs. 0 6 6.1 Cancerous Prostate) 15824 139677 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15825 139677 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15829 375958 _08, 09 (Lung, High Metastatic 0 9 6.44 Potential vs. Lung, Low Metastatic Potential) _21, 22 (Normal Prostate vs. 2 11 5.59 Cancerous Prostate) 15834 831812 _21,22 (Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15842 193373 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15843 400619 _08, 09 (Lung, High Metastatic 6 0 8.38 Potential vs. Lung, Low Metastatic Potential) 15844 831149 _21, 22 (Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15846 817503 _21, 22 (Normal Prostate vs. 18 4 4.43 Cancerous Prostate) 15853 648679 _23, 24 (Normal Lung vs. Lung 11 1 11.11 Tumor) _16, 17 (Colon Tumor vs. 79 0 80.23 Colon Metastasis) _15, 17 (Normal Colon vs. 7 0 7.51 Colon Metastasis) _15, 16 (Normal Colon vs. 7 79 10.68 Colon Tumor) 15856 373928 _21, 22 (Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15861 373928 _21, 22 (Normal Prostate vs. 7 0 6.88 Cancerous Prostate) 15864 372700 _19, 20 (Colon Tumor vs. 8 0 5.98 Colon Tumor Metastasis) _08, 09 (Lung, High Metastatic 3 50 11.93 Potential vs. Lung, Low Metastatic Potential) 15870 379105 _15, 16 (Normal Colon vs. 0 8 7.57 Colon Tumor) 15871 831188 _21, 22 (Normal Prostate vs. 0 8 8.13 Cancerous Prostate) 15875 831812 _21, 22 (Normal Prostate vs. 0 7 7.12 Cancerous Prostate) 15879 831026 _21, 22 (Normal Prostate vs. 0 10 10.17 Cancerous Prostate) 15881 380207 _21, 22 (Normal Prostate vs. 0 6 6.1 Cancerous Prostate) _08, 09 (Lung, High Metastatic 0 8 5.72 Potential vs. Lung, Low Metastatic Potential) 15882 819460 _21, 22 (Normal Prostate vs. 18 1 17.7 Cancerous Prostate) 15890 819201 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15891 374826 _15, 17 (Normal Colon vs. 5 20 3.73 Colon Metastasis) _08, 09 (Lung, High Metastatic 38 132 2.49 Potential vs. Lung, Low Metastatic Potential) _15, 16 (Normal Colon vs. 5 18 3.41 Colon Tumor) 15897 553242 _16, 17 (Colon Tumor vs. 0 6 5.91 Colon Metastasis) 15912 220584 _08, 09 (Lung, High Metastatic 1 12 8.59 Potential vs. Lung, Low Metastatic Potential) 15914 819498 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15919 819498 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15922 831160 _21, 22 (Normal Prostate vs. 0 12 12.2 Cancerous Prostate) 15925 831160 _21, 22 (Normal Prostate vs. 0 12 12.2 Cancerous Prostate) 15928 373298 _15, 17 (Normal Colon vs. 126 42 3.22 Colon Metastasis) _15, 16 (Normal Colon vs. 126 59 2.26 Colon Tumor) 15936 450262 _21, 22 (Normal Prostate vs. 0 8 8.13 Cancerous Prostate) 15937 484703 _21, 22 (Normal Prostate vs. 28 0 27.54 Cancerous Prostate) 15938 819498 _21, 22 (Normal Prostate vs. 6 0 5.9 Cancerous Prostate) 15939 406043 _21, 22 (Normal Prostate vs. 0 6 6.1 Cancerous Prostate) 15940 817500 _21, 22 (Normal Prostate vs. 2 18 9.15 Cancerous Prostate) 15941 818180 _21, 22 (Normal Prostate vs. 2 10 5.08 Cancerous Prostate) 15946 429009 _21, 22 (Normal Prostate vs. 8 1 7.87 Cancerous Prostate) 15950 383021 _21, 22 (Normal Prostate vs. 3 12 4.07 Cancerous Prostate) 15955 831580 _21, 22 (Normal Prostate vs. 0 6 6.1 Cancerous Prostate) 15977 763446 _21, 22 (Normal Prostate vs. 11 1 10.82 Cancerous Prostate) 15978 763446 _21, 22 (Normal Prostate vs. 11 1 10.82 Cancerous Prostate) 15980 763446 _21, 22 (Normal Prostate vs. 11 1 10.82 Cancerous Prostate) 15981 10154 _3, 4 (Breast, High Metastatic 3 317 108.1 Potential vs. Breast, Low Metastatic)

Example 80 Differential Expression of a Polynucleotides Associated with Metastatic Potential in Breast Cancer

Differential expression was examined in breast cancer cells having either high metastatic potential or low metastatic potential. A single cluster, Cluster Identification No. 10154, was identified as displaying low expression in the high metastatic potential breast cancer cells (Library 3), and significantly increased expression—approximately 100-fold higher—in the low metastatic potential cells (Library 4). Specifically, three clones were identified that were expressed in Library 3, the high metastatic potential breast cancer library, while 317 clones were expressed in Library 4, the low metastatic potential breast cancer library. The two sequences assigned to this particular cluster, SEQ ID NO:15981 and SEQ ID NO:15982, both displayed this differential expression, suggesting that the two sequences are likely associated with a single transcript.

SEQ ID NO: 15981 and SEQ ID NO: 15982 were then used as query sequences to search for homologous sequences in GenBank as described above. SEQ ID NO: 15981 displayed identity to the GenBank entry H72034 (SEQ ID NO: 15983) and SEQ ID NO: 15982 displayed identity to GenBank entry AA707002 (SEQ ID NO: 15984). SEQ ID NO: 15981 displays striking identity to the 3′ end of SEQ ID NO: 15983 (See FIGS. 1A and 1B), while SEQ ID NO: 15982 displays striking identity to the 5′ end of SEQ ID NO: 15984 (See FIG. 2). Clones of H72034 and AA707002 were ordered from the I.M.A.G.E. Consortium at the Lawrence Livermore National Laboratories (Livermore, Calif.) for further studies.

Restriction Mapping of Clones H72034 and AA707002

The newly identified sequences were digested with a number of different restriction endonucleases to construct a restriction map of each of the clones. An appropriate amount of each clone, SEQ ID NO: 15983 or SEQ ID NO: 15984, was digested with various enzymes, and the restriction fragments identified as follows:

Enzyme #Cuts Positions SEQ ID NO: 15983 AluI 5 331 1029 1422 1595 1977 BamHI 2 1836 2089 BstEII 1 936 BstXI 1 1033 HaeIII 12 145 300 453 497 582 780 1102 1536 1561 1722 1981 2062 HinfI 12 5 154 205 325 397 473 610 820 968 1295 1426 2066 KpnI 1 1938 MspI 6 78 739 1098 2038 2077 2093 NcoI 2 2013 2058 PstI 1 1501 PvuII 2 331 1422 Sau3AI 6 1270 1813 1819 1836 1894 2089 SphI 1 1870 XhoI 1 1413 SEQ ID NO: 15984 AluI 9 19 245 367 553 586 874 904 996 1214 BamHI 1 407 BglI 1 1056 BglII 1 475 BstEI 1 1108 HaeIII 10 153 348 485 867 518 628 780 867 915 1016 1312 HindIII 2 243 872 HinfI 1 1353 KpnI 1 132 MspI 2 1196 1261 PstI 1 823 PvuII 1 996 Sau3AI 7 66 407 475 504 750 850 1024

The restriction maps based on the identified sites can be used to determine the position of each clone relative to the genomic sequences, and to confirm the 5′-3′ orientation of the clones.

Amplification and Purification of Transcript

A transcript in this region upregulated in low metastatic cancers which contain sequences from SEQ ID NOS: 15983-15986-318 is identified using a technique such as polymerase chain reaction (PCR) amplification. Based on the sequences identified and the original sequences of the cluster, primers can be designed to isolate the full length cDNA from a library constructed from the breast cancer cell line with low metastatic potential.

A cDNA template for use in the amplification reaction is generated from total RNA isolated from the high metastatic breast cell line. RNA is reverse transcribed using oligo-dT primer to generate first strand cDNA. cDNA is synthesized by denaturing 3:1 of total RNA, 2:1 oligo-dT primer at 20:M, and 5:1 DEPC water for 8 minutes at 65° C. followed by reverse transcription at 52° C. for 1 hour in a reaction containing the denatured RNA/primer plus 4:1 15×cDNA buffer (GibcoBRL), 1:1 0.1 M dithiothreitol, 1:1 40 U/l RNAseOUT (GibcoBRL), 1:1 DEPC water, 2:1 10 mM dNTP (GibcoBRL), and 1:1 15 U/l Thermoscript reverse transcriptase (GibcoBRL). The reaction was terminated by a 5-min incubation at 85° C., and the RNA was removed by 1:1 2 U/l RNAse H at 37° C. for thirty minutes.

Based on the determined orientation of the clones, primers are designed to amplify a full-length clone corresponding to the differentially expressed transcript in this region. Forward primers that are used to amplify the full-length clone are taken from the 5′ end of SEQ ID NO:15683 as follows:

F1 5′-TGGGATATAGTCTCGTGGTGCG-3′ (SEQ ID NO: 15985) F2 5′-TGATTCGATGTCATCAGTCCCG-3′ (SEQ ID NO: 15986) Primer F1 is taken from residues 51-62 of SEQ ID NO: 15983, and primer F2 is taken from residues 212-233 Of SEQ ID NO:15683. Both forward primers are near the 5′ end of this sequence.

Reverse Primers are designed using sequences complementary to the 3′ end of clone 10154-3 as follows:

R1 5′-TGTGTCACAGCCAGACATGAGC (SEQ ID NO: 15987) R2 5′-TGCAAACATACACAGGGACCG (SEQ ID NO: 15988) Primer R1 is based on residues 573-552 of SEQ ID NO:15684, and R2 is based on residues 399-379 of SEQ ID NO:15684.

PCR is performed using a 5:1 aliquot of the first strand cDNA synthesis reaction, and a primer pair, e.g., F1 and R1, F1 and R2, F2 and R1, or F2 and R2. An open reading frame is amplified using 2:1 of the reverse transcription product as template in a PCR reaction containing 5:1 of 10×PCR buffer (GibcoBRL), 1:150 mM Mg₂SO₄, 1:110 mM dNTP, 1:1 F1 or F2 primer, 1 μl R1 primer, 2.5 U High Fidelity Platinum Taq DNA polymerase (GibcoBRL), and water to 50:1. The molecule is amplified using 30 rounds of amplification in a thermal cycler at the following temperatures: 1 minute at 95° C.; 1 minute at 55° C. and 2 minutes at 72° C. The 30 cycles was followed by a 10 minute extension at 72° C.

Following amplification of the sequences, the PCR products are loaded on a 1% TEA gel and subjected to gel purification. One or more bands can be isolated from the gel and the DNA was purified using a QIAquick® Gel Extraction Kit (Qiagen, Valencia, Calif.). The purified fragment was cloned into a bacterial vector and transformed into the bacterial strain DH5∀. Following cloning of the purified fragment(s), the DNA can be isolated and sequenced to confirm that a band corresponds to a transcript from this genetic region.

The reactions are carried out with two different 5′ and 3′ primers to increase the likelihood that the reaction will yield an amplification product. Other primers may also be designed from the predicted 5′ and/or 3′ end of the sequence, as will be apparent to one skilled in the art upon reading this disclosure, and thus other primers may be designed from the general region of SEQ ID NOS:317 and 318 that may yield better results than the disclosed primers.

In order to obtain additional sequences 5′ to the end of a partial cDNA, 5′ rapid amplification of cDNA ends (RACE) can be performed to ensure that the entire transcript has been identified. See PCR Protocols: A Guide to Methods and Applications, (1990) Academic Press, Inc. Following isolation of a cDNA using the F1-R1 or F2-R1 primer pairs, additional primers can be designed to perform RACE. The primers can be designed from the sequence of 10154-1 as follows:

5′-TTTAGCAGCACTAATGACTGTGGC-3′ (SEQ ID NO: 15989) 5′-CGCCGTGAATTACTGTGGATGG-3′ (SEQ ID NO: 15990) The two RACE primers are designed based residues 286-263 and 396-375 of SEQ ID NO:15983, respectively. These sequences can be used to obtain any transcript sequences 5′ to the amplification products obtained using the PCR protocol described above. Northern Analysis

Other techniques can be used for confirming differential expression of the full-length transcript. For example, a Northern Blot can be used to verify differential expression of SEQ ID NOS:15983 and 15984 in a breast cancer cells with low metastatic potential compared to breast cancer cells with high metastatic potential. Northern analysis can be accomplished by methods well-known in the art. Briefly, RNA is individually isolated from breast cancer cells having high metastatic potential and breast cancer cells having low metastatic potential, e.g., a product such as RNeasy Mini Kits (Qiagen, CA) or NucleoSpin® RNA II Kit (Clontech, Palo Alto, Calif.). The isolated RNA samples are For Northern analysis, RNA isolated from the cells was electrophoresed on a denaturing formaldehyde agarose gel and transferred onto a membrane such as a supported nitrocellulose membrane (Schleicher & Schuell).

Rapid-Hyb buffer (Amersham Life Science, Little Chalfont, England) with 5 mg/ml denatured single stranded sperm DNA is pre-warmed to 65° C. and the RNA blots are pre-hybridized in the buffer with shaking at 65° C. for 30 minutes. Gene-specific DNA probes (50 ng per reaction) labeled with [α-³²P]dCTP (3000 Ci/mmol, Amersham Pharmacia Biotech Inc., Piscataway, N.J.) (Prime-It RmT Kit, Stratagene, La Jolla, Calif.) and purified with ProbeQuant™ G-50 Micro Columns (Amersham Pharmacia Biotech Inc.) are added and hybridized to the blots with shaking at 65° C. for overnight. The blots are washed in 2×SSC, 0.1%(w/v) SDS at room temperature for 20 minutes, twice in 1×SSC, 0.1%(w/v) SDS at 65° C. for 15 minutes, then exposed to Hyperfilms (Amersham Life Science).

Example 81 Identification of Differentially Expressed Genes by Array Analysis with Patient Tissue Samples

Differentially expressed genes corresponding to the polynucleotides described herein were also identified by microarray hybridization analysis using materials obtained from patient tissue samples. The biological materials used in these experiments are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001). Table 127 (inserted following the last page of the Examples) provides information about each patient from which the samples were isolated, including: the Patient ID and Path ReportID, numbers assigned to the patient and the pathology reports for identification purposes; the anatomical location of the tumor (AnatomicalLoc); The Primary Tumor Size; the Primary Tumor Grade; the Histopathologic Grade; a description of local sites to which the tumor had invaded (Local Invasion); the presence of lymph node metastases (Lymph Node Metastasis); incidence of lymph node metastases (provided as number of lymph nodes positive for metastasis over the number of lymph nodes examined) (Incidence Lymphnode Metastasis); the Regional Lymphnode Grade; the identification or detection of metastases to sites distant to the tumor and their location (Distant Met & Loc); a description of the distant metastases (Description Distant Met); the grade of distant metastasis (Distant Met Grade); and general comments about the patient or the tumor (Comments). Adenoma was not described in any of the patients; adenoma dysplasia (described as hyperplasia by the pathologist) was described in Patient ID No. 695. Extranodal extensions were described in two patients, Patient ID Nos. 784 and 791. Lymphovascular invasion was described in seven patients, Patient ID Nos. 128, 278, 517, 534, 784, 786, and 791. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791.

Source of Polynucleotides on Arrays

Polynucleotides on Arrays

Polynucleotides spotted on the arrays were generated by PCR amplification of clones derived from cDNA libraries. The clones used for amplification were either the clones from which the sequences described herein were derived, or are clones having inserts with significant polynucleotide sequence overlap with the sequences described herein (SEQ ID NO:15667-15982) as determined by BLAST2 homology searching.

Microarray Design

Each array used in the examples below had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array. Spotting was accomplished using PCR amplified products from 0.5 kb to 2.0 kb and spotted using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides.

The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about 4 duplicate measurements for each clone, two of one color and two of the other, for each sample.

Microarray Analysis

cDNA probes were prepared from total RNA isolated from the patient cells described in above (Table 127). Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling. Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red).

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. For initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Table 128 below summarize the results of the differential expression analysis. Each table provides: the SEQ ID NO of the polynucleotide corresponding to the polynucleotide on the spot on the array; the Spot ID (an identifier assigned to the spot so as to distinguish it from spots on the same and different arrays), the number of patients for whom there was information obtained from the array (Num Ratios), and the percentage of patients in which expression was detected at greater than or equal to a two-fold increase (>=2×), greater than or equal to a five-fold increase (>=5×), or less than or equal to a ½-fold decrease (<=half×) relative to matched normal control tissue.

In general, a polynucleotide is said to represent a significantly differentially expressed gene between two samples when there is detectable levels of expression in at least one sample and the ratio value is greater than at least about 1.2 fold, preferably greater than at least about 1.5 fold, more preferably greater than at least about 2 fold, where the ratio value is calculated using the method described above.

A differential expression ratio of 1 indicates that the expression level of the gene in the tumor cell was not statistically different from expression of that gene in normal colon cells of the same patient. A differential expression ratio significantly greater than 1 in cancerous colon cells relative to normal colon cells indicates that the gene is increased in expression in cancerous cells relative to normal cells, indicating that the gene plays a role in the development of the cancerous phenotype, and may be involved in promoting metastasis of the cell. Detection of gene products from such genes can provide an indicator that the cell is cancerous, and may provide a therapeutic and/or diagnostic target.

Likewise, a differential expression ratio significantly less than 1 in cancerous colon cells relative to normal colon cells indicates that, for example, the gene is involved in suppression of the cancerous phenotype. Increasing activity of the gene product encoded by such a gene, or replacing such activity, can provide the basis for chemotherapy. Such gene can also serve as markers of cancerous cells, e.g., the absence or decreased presence of the gene product in a colon cell relative to a normal colon cell indicates that the cell may be cancerous.

TABLE 128 SEQ Num ID NO: SpotID Ratios >=2x >=5x <=halfx 15674 579 33 87.88 39.39 3.03 15678 22300 33 33.33 18.18 6.06 15692 21886 33 33.33 0.00 3.03 15730 9487 33 33.33 12.12 3.03 15914 28179 28 32.14 0.00 0.00 15919 28179 28 32.14 0.00 0.00 15938 28179 28 32.14 0.00 0.00 15958 9111 33 33.33 18.18 3.03 15961 19980 33 33.33 6.06 0.00 15975 23993 33 42.42 3.03 3.03

Deposit Information. The following materials were deposited with the American Type Culture Collection (CMCC=Chiron Master Culture Collection).

TABLE 124 Cell Lines Deposited with ATCC ATCC CMCC Cell Line Deposit Date Accession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containing specific clones, were assigned an “ES” number (internal reference) and deposited with the ATCC. Table 6 below provides the ATCC Accession Nos. of the ES deposits, all of which were deposited on or before May 13, 1999. The names of the clones contained within each of these deposits are provided in the Table 126 (inserted before the claims).

TABLE 125 Pools of Clones and Libraries Deposited with ATCC on or before Mar. 28, 2000 Cell Line CMCC ATCC ES75 5140 PTA-1102 ES76 5141 PTA-1103 ES77 5142 PTA-1104 ES78 5143 PTA-1105 ES79 5144 PTA-1106 ES80 5145 PTA-1107 ES81 5146 PTA-1108 ES82 5147 PTA-1109 ES83 5148 PTA-1110 ES84 5149 PTA-1111

TABLE 126 Library No. Clones es75 M00063947D:D01 M00063158A:A01 M00063517A:A04 M00063520D:E11 M00063638C:G12 M00063642B:A08 M00063686B:E07 M00063689D:E12 M00063781B:B10 M00063826A:D03 es76 M00063838B:G08 M00063838B:G08 M00063841A:B09 M00063886A:B06 M00063910D:A12 M00063912A:D06 M00063920D:H05 M00063928A:G09 M00063934B:E04 M00063945A:C03 es77 M00064032D:G04 M00064046A:G02 M00064053C:G04 M00064053D:F02 M00064082A:A08 M00064089B:F09 M00064132B:B07 M00064138A:F11 M00064161B:G04 M00064175B:B09 es78 M00064178C:C04 M00064179A:C04 M00064200D:E08 M00064248A:E02 M00064270B:B03 M00064271B:D03 M00063580C:A06 M00063594B:H07 M00064002C:F06 M00064002C:H09 es79 M00064003B:C10 M00064302A:D10 M00064309C:H09 M00064310D:F03 M00064322C:A10 M00064359B:H12 M00064390A:C05 M00064404A:B05 M00064404C:G05 M00064404D:A06 es80 M00064429D:B07 M00064446A:D11 M00064457D:C09 M00064476D:C04 M00064506A:C07 M00064514A:G10 M00064520A:F08 M00064579D:E11 M00064620C:D01 M00064624D:C09 es81 M00064633C:A03 M00064637B:F03 M00064690A:C04 M00064690A:C04 M00064714A:G03 M00064723D:H11 GKC10154-1 GKC10154-3 es82 M00063151A:G06 M00063852D:F07 M00063151D:B10 M00063888D:D05 M00063152C:B07 M00063888D:F02 M00063156D:H10 M00063890A:F11 M00063158A:E11 M00063890A:H04 M00063158A:E11 M00063891A:F11 M00063452A:F08 M00063892B:G02 M00063453B:F08 M00063898A:A10 M00063462D:D07 M00063915C:E01 M00063463D:B05 M00063919C:E07 M00063466C:C11 M00063920D:H02 M00063467D:H07 M00063922B:A12 M00063478C:D01 M00063925B:F04 M00063482A:A08 M00063926A:H04 M00063482A:F07 M00063931B:E10 M00063485A:E05 M00063931B:F07 M00063487C:C02 M00063932D:G08 M00063514C:D03 M00063934C:C10 M00063514C:E08 M00063938B:H07 M00063515B:F06 M00063939C:D06 M00063515B:H02 M00063939C:H01 M00063518D:A01 M00063940D:F09 M00063520D:D08 M00063940D:F09 M00063604A:B11 M00063941B:C12 M00063606C:B04 M00063943B:G12 M00063610D:C11 M00063949D:A05 M00063613D:C11 M00064021D:H01 M00063617D:F09 M00064025D:E07 M00063627C:F06 M00064025D:H12 M00063636A:E01 M00064033C:C11 M00063681B:C02 M00064033D:B01 M00063682A:C04 M00063843B:D07 M00063685A:C02 M00063848C:G11 M00063774A:D09 M00063852B:D08 M00063784A:H12 M00063818C:A09 M00063784C:E10 M00063828A:H12 M00063785C:F03 M00063828D:E05 M00063795C:D09 M00063839A:F01 M00063801B:D04 M00063841A:E08 M00063804C:A11 M00063805D:E05 M00063807A:D12 M00063810C:E03 es83 M00064043D:C09 M00063577C:C02 M00064048C:G12 M00063578B:E02 M00064053B:D09 M00063578C:A06 M00064057C:H10 M00063580D:B06 M00064059A:C11 M00063593A:D03 M00064060B:D03 M00063600C:C09 M00064079C:A10 M00063955C:F07 M00064082D:D10 M00063955D:F05 M00064083D:E05 M00063956A:F05 M00064086C:E01 M00063957A:E02 M00064090C:A02 M00063957A:E02 M00064090D:D09 M00063967C:A12 M00064105B:A03 M00063967D:G02 M00064106C:G03 M00063968D:G08 M00064113B:C04 M00063972C:E10 M00064115B:E12 M00063978B:B06 M00064119B:H10 M00063981D:A06 M00064119C:D12 M00063990A:D05 M00064122C:B06 M00063990A:D05 M00064126C:C02 M00063997C:B12 M00064126C:F12 M00063998C:E09 M00064136C:D12 M00064000B:C03 M00064144D:A07 M00064001A:B03 M00064151B:C07 M00064005D:A08 M00064159A:H03 M00064008A:B01 M00064165A:B12 M00064009A:C01 M00064171D:E05 M00064014D:H05 M00064171D:E05 M00064018C:E07 M00064172C:A02 M00064293D:B12 M00064173B:E01 M00064294D:F01 M00064176D:H10 M00063557D:C07 M00064178B:A05 M00063559D:G03 M00064178B:A05 M00063571B:G03 M00064180A:G03 M00063575B:G02 M00064186C:B03 M00063555B:D01 M00064188B:G08 M00063533A:C12 M00064194C:D02 M00063534C:A02 M00064212D:E04 M00063538D:B01 M00064260C:E05 M00063539C:C11 M00064268D:G03 M00064272C:G01 M00063163A:G04 M00063165A:C09 es84 M00064307B:G02 M00064564A:C02 M00064307C:G03 M00064568A:H06 M00064310C:A10 M00064569B:A09 M00064328B:H04 M00064569B:A09 M00064328B:H09 M00064571C:C04 M00064337D:F01 M0064577C:B120 M00064341A:C02 M00064579A:C06 M00064345A:A03 M00064593A:A05 M00064346C:B09 M00064593D:C01 M00064349D:H01 M00064601C:G07 M00064352C:H01 M00064601D:B05 M00064354A:A10 M00064605C:G05 M00064358A:G03 M00064610D:H01 M00064358C:D09 M00064620D:G05 M00064375B:G07 M00064624C:B03 M00064376A:A05 M00064631A:C07 M00064385D:C11 M00064631A:C07 M00064386B:C02 M00064631C:H11 M00064386B:C02 M00064636B:A04 M00064393B:H04 M00064649A:E04 M00064399A:E01 M00064650B:B07 M00064405B:C04 M00064652B:D09 M00064406B:H06 M00064675C:E09 M00064414D:D06 M00064678D:F05 M00064415B:G03 M00064693D:F08 M00064424B:C12 M00064723C:H04 M00064428B:A12 M00064723D:H03 M00064447B:A07 M00064723D:H03 M00064447B:C06 M00003773D:H02 M00064450C:E07 M00021929A:D03 M00064452D:E11 M00043134A:A05 M00064454A:H10 M00064534D:F06 M00064454C:B06 M00064550A:A07 M00064460C:B01 M00064554D:A03 M00064467B:D06 M00064526D:F05 M00064481C:F03 M00064527A:H07 M00064508A:B09 M00064530B:H02 M00064514D:F11 M00064532D:G06 M00064517B:F04 M00064520A:E04 M00064517B:F10 M00064520A:E04 M00064517C:F11 M00064524A:A09

TABLE 127 Table 8 Path Primary Primary Histo Incidence Regional Distant Descrip Patient Report Anatomical Tumor Tumor Path Local Lymphnode Lymphnode Lymphnode Met Distant Dist Met ID ID Loc Size Grade Grade Invasion Met Met Grade & Loc Met Grade Comment 15 21 Ascending 4.0 T3 G2 extending positive 3/8 N1 negative MX invasive colon into adenocarcinoma, subserosal moderately adipose differentiated; tissue focal perineural invasion is seen 52 71 Ascending 9.0 T3 G3 Invasion negative  0/12 N0 negative M0 Hyper colon through plastic muscularis polyp propria, in subserosal appendix. involvement; ileocec. valve involvement 121 140 sigmoid 6 T4 G2 Invasion of negative  0/34 N0 negative M0 Perineural muscularis invasion; propria into donut serosa, anastomosis involving negative. submucosa One of urinary tubulo bladder villous and one tubular adenoma with no high grade dysplasia. 125 144 Cecum 6 T3 G2 Invasion negative  0/19 N0 neagtive M0 patient through the history muscularis of propria into metastatic suserosal melanoma adipose tissue. Ileocecal junction. 128 147 Transverse 5.0 T3 G2 Invasion of positive 1/5 N1 negative M0 colon muscularis propria into percolonic fat 130 149 Splenic 5.5 T3 through positive 10/24 N2 negative M1 flexure wall and into surrounding adipose tissue 133 152 Rectum 5.0 T3 G2 Invasion negative 0/9 N0 negative M0 Small through separate muscularis tubular propria into adenoma non- (0.4 cm) peritonealized pericolic tissue; gross configuration is annular. 141 160 Cecum 5.5 T3 G2 Invasion of positive  7/21 N2 positive adenocarcinoma M1 Perineural muscularis (Liver) consistant invasion propria into with identified pericolonic primary adjacent adipose to tissue, but metastatic not through adenocarcinoma. serosa. Arising from tubular adenoma. 156 175 Hepatic 3.8 T3 G2 Invasion positive  2/13 N1 negative M0 Separate flexure through tubolo mucsularis villous propria into and subserosa/pericolic tubular adipose, adenomas no serosal involvement. Gross configuration annular. 228 247 Rectum 5.8 T3 G2 to Invasion positive 1/8 N1 negative MX Hyper G3 through plastic muscularis polyps propria to involve subserosal, perirectoal adipose, and serosa 264 283 Ascending 5.5 T3 G2 Invasion negative  0/10 N0 negative M0 Tubul colon through ovillous muscularis adenoma propria into with subserosal high adipose grade tissue. dysplasia 266 285 Transverse 9 T3 G2 Invades negative  0/15 N1 positive 0.4 cm, MX colon through (Mesenteric may muscularis deposit) represent propria to lymphnode involve completely pericolonic replaced adipose, by extends to tumor serosa. 268 287 Cecum 6.5 T2 G2 Invades full negative  0/12 N0 negative M0 thickness of muscularis propria, but mesenteric adipose free of malignancy 278 297 Rectum 4 T3 G2 Invasion positive  7/10 N2 negative M0 Descending into colon perirectal polyps, adipose no tissue. HGD or carcinoma identified.. 295 314 Ascending 5.0 T3 G2 Invasion negative  0/12 N0 negative M0 Melanosis colon through coli muscularis and propria into diverticular percolic disease. adipose tissue. 339 358 Restosigmo 6 T3 G2 Extends negative 0/6 N0 negative M0 1 id into hyperplastic perirectal polyp fat but identified does not reach serosa 341 360 Ascending 2 cm T3 G2 Invasion negative 0/4 N0 negative MX colon invasive through muscularis propria to involve pericolonic fat. Arising from villous adenoma. 356 375 Sigmoid 6.5 T3 G2 Through negative 0/4 N0 negative M0 colon wall into subserosal adipose tissue. No serosal spread seen. 360 412 Ascending 4.3 T3 G2 Invasion positive 1/5 N1 negative M0 Two colon thru mucosal muscularis polyps propria to pericolonic fat 392 444 Ascending 2 T3 G2 Invasion positive 1/6 N1 positive Macro M1 Tumor colon through (Liver) vesicular arising muscularis and at propria into microvesicular prior subserosal steatosis ileocolic adipose surgical tissue, not anastomosis. serosa. 393 445 Cecum 6.0 T3 G2 Cecum, negative  0/21 N0 Negative M0 invades through muscularis propria to involve subserosal adipose tissue but not serosa. 413 465 Ascending 4.8 T3 G2 Invasive negative 0/7 N0 positive adenocarcinoma M1 rediagnosis colon through (Liver) in of muscularis multiple oophorectomy to involve slides path periserosal to fat; metastatic abutting colon ileocecal cancer. junction. 505 383 7.5 cm T3 G2 Invasion positive  2/17 N1 positive moderately M1 Anatomical max dim through (Liver) differentiated location muscularis adenocarcinoma, of propria consistant report. involving with Evidence pericolic primar of adipose, chronic serosal colitis. surface uninvolved 517 395 Sigmoid 3 T3 G2 penetrates positive 6/6 N2 negative M0 No muscularis mention propria, of involves distant pericolonic met in fat. report 534 553 Ascending 12 T3 G3 Invasion negative 0/8 N0 negative M0 Omentum colon through the with muscularis fibrosis propria and involving fat pencolic necrosis. fat. Serosa Small free of bowel tumor. with acute and chronic serositis, focal abscess and adhesion. 546 565 Ascending 5.5 T3 G2 Invasion positive  6/12 N2 positive metastatic M1 colon through (Liver) adenocarcinoma muscularis propria extensively through submucosal and extending to serosa. 577 596 Cecum 11.5 T3 G2 Invasion negative  0/58 N0 negative M0 Appendix through the dilated bowel wall, and into fibrotic, suberosal but adipose. not Serosal involved surface free by of tumor. tumor 695 714 Cecum 14 T3 G2 extending negative  0/22 N0 negative MX tubular through adenoma bowel wall and into serosalfat hyperplstic polypspresent, moderately differentiated adenoma with mucinous diferentiation (% not stated) 784 803 Ascending 3.5 T3 G3 through positive  5/17 N2 positive M1 invasive colon muscularis (Liver) poorly propria into differentiated pericolic adenosquamous soft tissues carcinoma 786 805 Descending 9.5 T3 G2 through negative  0/12 N0 positive M1 moderately colon muscularis (Liver) differentiated propria into invasive pericolic adenocarcinoma fat, but not at serosal surface 791 810 Ascending 5.8 T3 G3 through the positive 13/25 N2 positive M1 poorly colon muscularis (Liver) differentiated propria into invasive pericolic fat colonic adenocarcinoma 888 908 Ascending 2.0 T2 G1 into positive  3/21 N0 positive M1 well- colon muscularis (Liver) to propria moderately- differentiated adenocarcinoma; this patient has tumors of the ascending colon and the sigmoid colon 889 909 Cecum 4.8 T3 G2 through positive 1/4 N1 positive M1 moderately muscularis (Liver) differentiated propria int adenocarcinoma subserosal tissue

The deposits described herein are provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. §112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where the ATCC deposit is composed of a pool of cDNA clones or a library of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones in the pool or library were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

Example 82 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

Candidate polynucleotides that may represent novel polynucleotides were obtained from cDNA libraries generated from selected cell lines and patient tissues. In order to obtain the candidate polynucleotides, mRNA was isolated from several selected cell lines and patient tissues, and used to construct cDNA libraries. The cells and tissues that served as sources for these cDNA libraries are summarized in Table 129 below.

Human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863) is derived from the KM12C cell line. The KM12C cell line (Morikawa et al. Cancer Res. (1988) 48:1943-1948), which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B2 surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KM12L4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246).

The MDA-MB-231 cell line (Brinkley et al. Cancer Res. (1980) 40:3118-3129) was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)).

The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cell lines were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

TABLE 129 Description of cDNA Libraries Number Library of Clones (lib #) Description in Library 0 Artificial library composed of deselected clones (clones with no 673 associated variant or cluster) 1 Human Colon Cell Line Km12 L4: High Metastatic Potential 308731 (derived from Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic Potential 284771 3 Human Breast Cancer Cell Line MDA-MB-231: High Metastatic 326937 Potential; micro-mets in lung 4 Human Breast Cancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung Cancer Cell Line MV-522: High Metastatic Potential 223620 9 Human Lung Cancer Cell Line UCP-3: Low Metastatic Potential 312503 12 Human microvascular endothelial cells (HMEC) - UNTREATED 41938 (PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells (HMEC) - bFGF TREATED 42100 (PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells (HMEC) - VEGF TREATED 42825 (PCR (OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTED PCR (OligodT) 282722 cDNA library) 16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR (OligodT) 298831 cDNA library) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467 (MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED PCR (OligodT) 36216 cDNA library) 19 Colon Tumor - UC#3 Patient (MICRODISSECTED PCR (OligodT) 41388 cDNA library) 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 (MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived from normal prostate epithelium 164801 22 WOca Cells derived from Gleason Grade 4 prostate cancer 162088 epithelium 23 Normal Lung Epithelium of Patient #1006 (MICRODISSECTED 306198 PCR (OligodT) cDNA library) 24 Primary tumor, Large Cell Carcinoma of Patient #1006 309349 (MICRODISSECTED PCR (OligodT) cDNA library) 25 Normal Prostate Epithelium from Patient IF97-26811 279444 26 Prostate Cancer Epithelium Gleason 3 + 3 Patient IF97-26811 269406 27 Normal Breast Epithelium from Patient 515 239494 28 Primary Breast tumor from Patient 515 259960 29 Lymph node metastasis from Patient 515 326786 30 Normal Prostate Epithelium from Chiron Patient ID 884 298431 31 Prostate Cancer Epithelium (Gleason 4 + 4) from Chiron Patient ID 331941 884

Characterization of Sequences in the Libraries

After using the software program Phred (ver 0.000925.c, Green and Weing, ©1993-2000) to select those polynucleotides having the best quality sequence, the polynucleotides were compared against the public databases to identify any homolgous sequences. The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the BLASTX masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relatively little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. The remaining sequences were then used in a BLASTN vs. GenBank search; sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10e-40 were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the GenBank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10e-5), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10e-5). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10e-40 were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10e-40 were discarded. Sequences with a p value of less than 1×10e-65 when compared to a database sequence of human origin were also excluded. Second, a BLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p value less than 1×10e-40, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10e-111 in relation to a database sequence of human origin were specifically excluded. The final result provided the 8064 sequences listed as SEQ ID NOS 15991-22000 in the accompanying Sequence Listing and summarized in Table 130 (inserted prior to claims). Each identified polynucleotide represents sequence from at least a partial mRNA transcript.

Summary of Polynucleotides of the Invention

Table 130 (inserted prior to claims) provides a summary of polynucleotides isolated as described. Specifically, Table 130 provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for use in the present specification; 2) the Cluster Identification No. (“CLUSTER”); 3) the Sequence Name assigned to each sequence; 3) the sequence name (“SEQ NAME”) used as an internal identifier of the sequence; 4) the orientation of the sequence (“ORIENT”) (either forward (F) or reverse (R)); 5) the name assigned to the clone from which the sequence was isolated (“CLONE ID”); and the name of the library from which the sequence was isolated (“LIBRARY”), where the notation indicates that name of the cell line or patient sample (e.g., UC2-NormColon indicates the sequence was isolated from normal colon tissue of the patient assigned the identification UC#2). Because at least some of the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides may represent different regions of the same mRNA transcript and the same gene and/or may be contained within the same clone. Thus, for example, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene

Example 83 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS: 15991-22000 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in either the GenBank (nucleotide sequences) or Non-Redundant Protein (amino acid sequences) databases. Query and individual sequences were aligned using the BLAST 2.0 programs, available over the world wide at a site sponsored by the National Center for Biotechnology Information, which is supported by the National Library of Medicine and the National Institutes of Health (see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402). The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the BLASTX program for masking low complexity as described above in Example 82.

Tables 131A and 131B (inserted prior to claims) provides the alignment summaries having a p value of 1×10e-2 or less indicating substantial homology between the sequences of the present invention and those of the indicated public databases. Specifically, Table 131A provides the SEQ ID NO of the query sequence, the accession number of the GenBank database entry of the homologous sequence, and the individual p value of each alignment. Table 131A provides the SEQ ID NO of the query sequence, the accession number of the Non-Redundant Protein database entry of the homologous sequence, and the individual p value of each alignment. The alignments provided in Tables 131A and 131B are the best available alignment to a DNA or amino acid sequence at a time just prior to filing of the present specification. The activity of the polypeptide encoded by the SEQ ID NOS listed in these tables can be extrapolated to be substantially the same or substantially similar to the activity of the reported nearest neighbor or closely related sequence. The accession number of the nearest neighbor is reported, providing a publicly available reference to the activities and functions exhibited by the nearest neighbor. The public information regarding the activities and functions of each of the nearest neighbor sequences is incorporated by reference in this application. Also incorporated by reference is all publicly available information regarding the sequence, as well as the putative and actual activities and functions of the nearest neighbor sequences listed in Tables 131A and 131B and their related sequences. The search program and database used for the alignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of the corresponding polynucleotide. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of the corresponding polynucleotides.

Example 83.5 Members of Protein Families

SEQ ID NOS:15991-22000 were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein family (and thus represent members of these protein families) and/or comprising a known functional domain. Table 132 (inserted before claims) provides the SEQ ID NO: of the query sequence, the Sequence Name, the Cluster to which the sequence is assigned, a brief description of the profile hit, the orientation (Direction, “Dir”) of the query sequence with respect to the individual sequence) where forward (for) indicates that the alignment is in the same direction (left to right) as the sequence provided in the Sequence Listing and reverse (rev) indicates that the alignment is with a sequence complementary to the sequence provided in the Sequence Listing), and the score of the profile hit.

Some polynucleotides exhibited multiple profile hits where the query sequence contains overlapping profile regions, and/or where the sequence contains two different functional domains. Each of the profile hits of Table 132 is described in more detail below. The acronyms for the profiles (provided in parentheses) are those used to identify the profile in the Pfam, Prosite, and InterPro databases. The Pfam database can be accessed through web sites supported by Genome Sequencing Center at the Washington University School of Medicine or by the European Molecular Biology Laboratories in Heidelberg, Germany. The Prosite database can be accessed at the ExPASy Molecular Biology Server on the internet. The InterPro database can be accessed at a web site supported by the EMBL European Bioinformatics Institute. The public information available on the Pfam, Prosite, and InterPro databases regarding the various profiles, including but not limited to the activities, function, and consensus sequences of various proteins families and protein domains, is incorporated herein by reference. Table 132

SEQ ID NO SEQ NAME CLUSTER PROFILE NAME DIR SCORE 15996 2102.B18.gz43_275316 558147 Ets_Cterm for 19.58 15999 2103.M06.gz43_275519 377696 protkinase for 20.71 16028 2153.K14.gz43_278937 372952 Dead_box_helic for 172.21 16029 2154.M04.gz43_279163 377696 protkinase for 20.71 16051 2165.H06.gz43_280342 393635 zf-c2h2 for 33.96 16059 2166.J11.gz43_281368 377696 protkinase for 20.71 16098 2118.A09.gz43_307025 446397 bzip for 19.15 16107 2131.I13.gz43_308085 34071 wd40 for 37.45 16108 2131.B14.gz43_308094 221686 protkinase for 33.14 16218 1573.F18.gz43_208848 639849 PH for 42.77 16219 1573.K19.gz43_208869 486238 protkinase rev 45.41 16405 1585.G22.gz43_210545 412416 Dead_box_helic for 49.67 16435 1587.B06.gz43_211440 446984 ANK rev 23.12 16476 1597.G06.gz43_212233 639593 defensins rev 18.27 16477 1597.J06.gz43_212236 557975 ANK for 35.63 16492 1597.F18.gz43_212424 596882 zf-c2h2 rev 18.13 16690 1694.M19.gz43_214375 425923 zf-c2h2 for 32.76 16837 1706.P07.gz43_216138 639901 zf-c2h2 for 19.43 16867 1707.J02.gz43_216453 550237 zf-ccch for 26.74 17501 1755.P24.gz43_223395 606129 rvt for 37.6 17704 1790.C14.gz43_226997 727150 bzip for 24.2 18024 1828.J19.gz43_232472 728303 zf-c2h2 rev 18.19 18028 1828.P21.gz43_232510 509678 Retvir_asp_protease for 28.5 18044 1838.N05.gz43_233020 481614 zf-c2h2 for 18.52 18504 1888.O06.gz43_240269 451764 rvt for 49.99 18963 1924.H18.gz43_245579 499700 7tm_1 rev 73.7 19003 1935.E18.gz43_246500 490805 ANK rev 28.74 19130 1981.O19.gz43_248062 558949 zf-c3hc4 rev 19.16 19393 1958.N12.gz43_250647 556308 zf-c2h2 for 40.77 19514 1923.M22.gz43_252963 562603 zf-c2h2 rev 42.42 19643 1995.C03.gz43_256117 562152 zf-c2h2 rev 18.97 19679 1995.P13.gz43_256290 562989 EGF rev 19.4 19713 1995.B24.gz43_256452 556632 zf-c2h2 rev 20.64 19804 2007.F09.gz43_257778 560652 zf-c2hc rev 21.49 19921 2008.F18.gz43_258308 550497 bzip for 20.27 20141 1669.G11.gz43_260853 503275 protkinase rev 43.25 20346 1682.O17.gz43_262495 450211 bzip rev 26.06 20363 1682.F21.gz43_262550 546740 EFhand rev 18.72 20678 2018.K14.gz43_264760 432970 zf-c2h2 for 48.43 20969 2041.C09.gz43_266976 556632 zf-c2h2 rev 20.88 21457 2067.I20.gz43_271090 551617 7tm_1 rev 19.77 21498 2068.F14.gz43_271375 561707 7tm_1 rev 24.27 21512 2068.D17.gz43_271421 554774 tgf-beta for 18.24 21746 2176.J17.gz43_281945 412416 Dead_box_helic for 37.64 21991 1561.C22.gz43_314731 447072 PH for 31.95

Example 84 Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention were assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 129 above provides a summary of these libraries, including the shortened library name, the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in, the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences Between Proportions,” pp 296-298 (1974).

Using this approach, a number of polynucleotide sequences were identified as being differentially expressed between, for example, cells derived from high metastatic potential cancer tissue and low metastatic cancer cells, and between cells derived from metastatic cancer tissue and normal tissue. Evaluation of the levels of expression of the genes corresponding to these sequences can be valuable in diagnosis, prognosis, and/or treatment (e.g., to facilitate rationale design of therapy, monitoring during and after therapy, etc.). Moreover, the genes corresponding to differentially expressed sequences described herein can be therapeutic targets due to their involvement in regulation (e.g., inhibition or promotion) of development of, for example, the metastatic phenotype. For example, sequences that correspond to genes that are increased in expression in high metastatic potential cells relative to normal or non-metastatic tumor cells may encode genes or regulatory sequences involved in processes such as angiogenesis, differentiation, cell replication, and metastasis.

Detection of the relative expression levels of differentially expressed polynucleotides described herein can provide valuable information to guide the clinician in the choice of therapy. For example, a patient sample exhibiting an expression level of one or more of these polynucleotides that corresponds to a gene that is increased in expression in metastatic or high metastatic potential cells may warrant more aggressive treatment for the patient. In contrast, detection of expression levels of a polynucleotide sequence that corresponds to expression levels associated with that of low metastatic potential cells may warrant a more positive prognosis than the gross pathology would suggest.

A number of polynucleotide sequences of the present invention are differentially expressed between human microvascular endothelial cells (HMVEC) that have been treated with growth factors relative to untreated HMVEC. Sequences that are differentially expressed between growth factor-treated HMVEC and untreated HMVEC can represent sequences encoding gene products involved in angiogenesis, metastasis (cell migration), and other development and oncogenic processes. For example, sequences that are more highly expressed in HMVEC treated with growth factors (such as bFGF or VEGF) relative to untreated HMVEC can serve as drug targets for chemotherapeutics, e.g., decreasing expression of such up-regulated genes or inhibiting the activity of the encoded gene product would serve to inhibit tumor cell angiogenesis. Detection of expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The differential expression of the polynucleotides can thus be used as, for example, diagnostic and/or prognostic markers, for risk assessment, patient treatment and the like. These polynucleotides can also be used in combination with other molecular and/or biochemical markers.

The differential expression data for polynucleotides of the invention that have been identified as being differentially expressed across various combinations of the libraries described above is summarized in Table 133 (inserted prior to the claims). Table 133 provides: 1) the Sequence Identification Number (“SEQ ID NO”) assigned to the polynucleotide; 2) the cluster (“CLUSTER”) to which the polynucleotide has been assigned as described above; 3) the library comparisons that resulted in identification of the polynucleotide as being differentially expressed (“PAIR AB”), where the cDNA libraries used are referenced by their library numbers; 4) the number of clones corresponding to the polynucleotide in the first library listed (“CLONES A”); 5) the number of clones corresponding to the polynucleotide in the second library listed (“CLONES B”); 6) the “RATIO PLUS” where the comparison resulted in a finding that the number of clones in library A is greater than the number of clones in library B; and 7) the “RATIO MINUS” where the comparison resulted in a finding that the number of clones in library B is greater than the number of clones in library A.

Detection of expression of genes that correspond to the above polynucleotides may be of particular interest in diagnosis, prognosis, risk assessment, and monitoring of treatment. Furthermore, differential expression of a specific gene across multiple libraries can also be indicative of a gene whose expression is associated with, for example, suppression of the metastatic phenotype or with development of the cell toward a metastatic phenotype. For example, SEQ ID NO:19734 corresponds to a gene that is expressed at relatively higher levels in metastasized colon tumor than in normal colon tissue. Thus a relatively increased level of expression of the gene corresponding to SEQ ID NO: 19734 may be used as marker of a metastatic or pre-metastatic colon cells either alone or in combination with other markers.

Some polynucleotides exhibited similar differential expression trends in libraries of different tissue origin (see, e.g., SEQ ID NO:17327). These data suggest that the differential expression patterns of some genes associated with development of tumors indicate a role for those genes that is non-specific to the tissue of origin.

Example 85 Detection of Differential Expression Using Arrays

mRNA isolated from samples of cancerous and normal colon tissue obtained from patients were analyzed to identify genes differentially expressed in cancerous and normal cells. Normal and cancerous cells collected from cryopreserved patient tissues were isolated using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001).

Table 134 (inserted before the claims) provides information about each patient from which colon tissue samples were isolated, including: the Patient ID (“PT ID”) and Path ReportID (}Path ID”), which are numbers assigned to the patient and the pathology reports for identification purposes; the group (“Grp”) to which the patients have been assigned; the anatomical location of the tumor (“Anatom Loc”); the primary tumor size (“Size”); the primary tumor grade (“Grade”); the identification of the histopathological grade (“Histo Grade”); a description of local sites to which the tumor had invaded (“Local Invasion”); the presence of lymph node metastases (“LN Met”); the incidence of lymph node metastases (provided as a number of lymph nodes positive for metastasis over the number of lymph nodes examined) (“Incidence Lymphnode Met”); the “Regional Lymphnode Grade”; the identification or detection of metastases to sites distant to the tumor and their location (“Dist Met & Loc”); the grade of distant metastasis (“Dist Met Grade”); and general comments about the patient or the tumor (“Comments”). Histophatology of all primary tumors indicated the tumor was adenocarcinmoa except for Patient ID Nos. 130 (for which no information was provided), 392 (in which greater than 50% of the cells were mucinous carcinoma), and 784 (adenosquamous carcinoma). Extranodal extensions were described in three patients, Patient ID Nos. 784, 789, and 791. Lymphovascular invasion was described in Patient ID Nos. 128, 278, 517, 534, 784, 786, 789, 791, 890, and 892. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791. Table 135 (below) provides information about the patients from whom the prostate tissue was isolated.

TABLE 135 Prostate paitent data. Prostate Patient ID Tumor Gleason Grade Normal Prostate Description 96 3 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 282 4 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 286 3 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 294 3 + 4 Adenocarcinoma Normal prostate; Benign hyperplasia 362 3 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 428 4 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 492 3 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 492 3 + 3 Adenocarcinoma Normal prostate; Benign hyperplasia 493 3 + 4 Adenocarcinoma Normal prostate; Benign hyperplasia 510 3 + 3 Adenocarcinoma Normal Prostate; Benign hyperplasia

Identification of Differentially Expressed Genes

cDNA probes were prepared from total RNA isolated from the patient cells described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. For polynucleotides described herein, the microarray spot contained a clone having a cDNA from which the sequence was derived. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample.

Table 136 (inserted before the claims) describes sequences present on the arrays. Table 136 includes: 1) athe SEQ ID NO of the sequence of the polynucleotide; and 2) the Spot ID, which is a unique identifier for each spot obtaining target sequence of interest on all arrays used.

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Table 136 (inserted before the claims) provides the results for gene products differentially expressed in the colon tumor samples relative to normal tissue samples. Table 136 includes: 1) the SEQ ID NO; 2) the spot identification number (“SpotID”); 3) the percentage of patients tested in which expression levels of the gene (as detected using the corresponding clone) was at least 2-fold greater in cancerous colon tissue (primary colon tumor) than in matched normal tissue (“Colon>2×T/N”); 4) the percentage of patients tested in which expression levels of the gene was less than or equal to one-half of the expression level in matched normal cells (“Colon<=half×T/N”); and 5) the colon number ratios, indicating the number of patients upon which the provided ratios was based.

TABLE 136 SEQ ID T/N Colon T/N Colon T/N Colon Num NO SpotID >2x <halfx Ratios 15996 43971 0.0 75.0 8.0 16021 40453 0.0 42.9 7.0 16030 40457 0.0 71.4 7.0 16034 46308 0.0 50.0 8.0 16040 45610 0.0 62.5 8.0 16060 42816 0.0 50.0 8.0 16062 44673 0.0 50.0 8.0 16064 42422 0.0 37.5 8.0 16067 43983 0.0 37.5 8.0 16071 44679 0.0 50.0 8.0 16074 42418 0.0 37.5 8.0 16123 39755 0.0 42.9 7.0 16129 44916 0.0 50.0 8.0 16137 45618 0.0 37.5 8.0 16139 44926 0.0 50.0 8.0 16142 44216 0.0 37.5 8.0 16143 38367 0.0 42.9 7.0 16148 38357 0.0 57.1 7.0 16151 41869 0.0 42.9 7.0 16152 43508 0.0 37.5 8.0 16154 38365 0.0 57.1 7.0 16156 39069 0.0 42.9 7.0 16161 39061 0.0 57.1 7.0 16170 39767 0.0 42.9 7.0 16174 43881 0.0 37.5 8.0 16176 43873 0.0 37.5 8.0 16185 39769 0.0 57.1 7.0 16186 39775 0.0 57.1 7.0 16187 46330 0.0 37.5 8.0 16188 42471 0.0 37.5 8.0 16190 41173 0.0 42.9 7.0 16192 42479 0.0 50.0 8.0 16206 39621 0.0 42.9 7.0 16207 46007 0.0 50.0 8.0 16208 46015 0.0 62.5 8.0 16215 45301 0.0 37.5 8.0 16218 45303 0.0 37.5 8.0 16240 41033 0.0 57.1 7.0 16250 41035 0.0 57.1 7.0 16258 41027 0.0 42.9 7.0 16264 41737 0.0 42.9 7.0 16291 39647 0.0 42.9 7.0 16297 38943 0.0 42.9 7.0 16299 38939 0.0 42.9 7.0 16305 44939 0.0 37.5 8.0 16314 42827 0.0 37.5 8.0 16316 38231 0.0 42.9 7.0 16324 42819 0.0 37.5 8.0 16342 43521 0.0 62.5 8.0 16348 45633 0.0 50.0 8.0 16354 44931 0.0 50.0 8.0 16355 45635 0.0 50.0 8.0 16356 46345 0.0 37.5 8.0 16380 44947 0.0 50.0 8.0 16381 44247 0.0 50.0 8.0 16393 43501 0.0 37.5 8.0 16396 43489 0.0 50.0 8.0 16397 44951 0.0 37.5 8.0 16403 41755 0.0 42.9 7.0 16410 43541 0.0 37.5 8.0 16414 44953 0.0 50.0 8.0 16416 46365 0.0 62.5 8.0 16422 44909 0.0 50.0 8.0 16425 38210 0.0 42.9 7.0 16433 38928 0.0 42.9 7.0 16434 44911 0.0 50.0 8.0 16436 46361 0.0 50.0 8.0 16440 39632 0.0 42.9 7.0 16442 39620 0.0 42.9 7.0 16445 46363 0.0 62.5 8.0 16448 41736 0.0 57.1 7.0 16454 38944 0.0 42.9 7.0 16457 45605 0.0 62.5 8.0 16458 45609 0.0 100.0 8.0 16461 38228 0.0 57.1 7.0 16462 41740 0.0 42.9 7.0 16466 41032 0.0 42.9 7.0 16470 39638 0.0 57.1 7.0 16472 41760 0.0 42.9 7.0 16480 41754 0.0 71.4 7.0 16486 39980 0.0 57.1 7.0 16487 46315 0.0 37.5 8.0 16497 40674 0.0 42.9 7.0 16499 38566 0.0 57.1 7.0 16509 38590 0.0 42.9 7.0 16529 42813 0.0 37.5 8.0 16544 43515 0.0 50.0 8.0 16548 41400 0.0 42.9 7.0 16550 40702 0.0 42.9 7.0 16553 40000 0.0 42.9 7.0 16563 38185 0.0 42.9 7.0 16572 39587 0.0 42.9 7.0 16577 44925 0.0 50.0 8.0 16582 39597 0.0 57.1 7.0 16583 39593 0.0 42.9 7.0 16593 38893 0.0 42.9 7.0 16596 42842 0.0 62.5 8.0 16597 43540 0.0 50.0 8.0 16601 42840 0.0 50.0 8.0 16604 43548 0.0 37.5 8.0 16607 43538 0.0 50.0 8.0 16608 46340 0.0 37.5 8.0 16634 39586 0.0 42.9 7.0 16641 45656 0.0 37.5 8.0 16644 44254 0.0 50.0 8.0 16645 45652 0.0 37.5 8.0 16656 46285 0.0 37.5 8.0 16657 40290 0.0 42.9 7.0 16658 40304 0.0 42.9 7.0 16670 39592 0.0 42.9 7.0 16672 44950 0.0 37.5 8.0 16681 45571 0.0 37.5 8.0 16692 45654 0.0 37.5 8.0 16693 45660 0.0 37.5 8.0 16695 40292 0.0 42.9 7.0 16701 40294 0.0 42.9 7.0 16712 46364 0.0 37.5 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0.0 42.9 7.0 19701 39401 0.0 42.9 7.0 19706 39405 0.0 42.9 7.0 19713 38697 0.0 42.9 7.0 19826 42213 0.0 42.9 7.0 19860 38717 0.0 42.9 7.0 19871 38719 0.0 42.9 7.0 19909 38707 0.0 42.9 7.0 19924 38713 0.0 42.9 7.0 19945 39419 0.0 42.9 7.0 20018 42274 0.0 42.9 7.0 20029 38772 0.0 42.9 7.0 20031 42286 0.0 42.9 7.0 20035 38770 0.0 42.9 7.0 20045 42282 0.0 42.9 7.0 20049 42284 0.0 42.9 7.0 20087 38774 0.0 42.9 7.0 20114 40313 0.0 42.9 7.0 20121 45625 0.0 50.0 8.0 20127 41005 0.0 42.9 7.0 20130 38203 0.0 42.9 7.0 20135 46325 0.0 37.5 8.0 20136 39611 0.0 42.9 7.0 20137 40309 0.0 57.1 7.0 20143 45619 0.0 37.5 8.0 20153 41697 0.0 42.9 7.0 20156 38899 0.0 42.9 7.0 20160 38903 0.0 42.9 7.0 20161 41003 0.0 42.9 7.0 20163 40995 0.0 42.9 7.0 20165 46321 0.0 37.5 8.0 20167 41017 0.0 42.9 7.0 20172 42474 0.0 50.0 8.0 20185 42478 0.0 37.5 8.0 20187 41015 0.0 42.9 7.0 20202 41713 0.0 42.9 7.0 20204 42480 0.0 37.5 8.0 20207 43886 0.0 37.5 8.0 20218 43888 0.0 37.5 8.0 20230 44586 0.0 37.5 8.0 20242 43188 0.0 37.5 8.0 20244 45304 0.0 62.5 8.0 20253 45996 0.0 37.5 8.0 20265 46016 0.0 37.5 8.0 20267 43198 0.0 37.5 8.0 20269 44606 0.0 50.0 8.0 20272 42496 0.0 50.0 8.0 20275 43900 0.0 37.5 8.0 20276 44608 0.0 37.5 8.0 20278 43902 0.0 75.0 8.0 20280 46006 0.0 37.5 8.0 20283 43192 0.0 37.5 8.0 20286 42490 0.0 37.5 8.0 20289 43896 0.0 37.5 8.0 20295 42492 0.0 37.5 8.0 20297 46008 0.0 50.0 8.0 20307 39941 0.0 42.9 7.0 20314 42053 0.0 42.9 7.0 20331 38541 0.0 42.9 7.0 20333 42055 0.0 42.9 7.0 20340 39241 0.0 42.9 7.0 20361 40647 0.0 42.9 7.0 20374 41355 0.0 42.9 7.0 20376 39261 0.0 42.9 7.0 20385 39967 0.0 42.9 7.0 20387 38559 0.0 42.9 7.0 20390 40663 0.0 42.9 7.0 20393 40669 0.0 42.9 7.0 20398 39263 0.0 42.9 7.0 20411 44930 0.0 37.5 8.0 20414 42071 0.0 42.9 7.0 20415 45638 0.0 37.5 8.0 20418 44228 0.0 37.5 8.0 20419 41371 0.0 42.9 7.0 20424 45640 0.0 50.0 8.0 20425 44163 0.0 37.5 8.0 20426 44171 0.0 37.5 8.0 20429 42818 0.0 50.0 8.0 20430 45634 0.0 50.0 8.0 20431 45644 0.0 50.0 8.0 20437 43471 0.0 37.5 8.0 20438 43536 0.0 62.5 8.0 20443 44944 0.0 37.5 8.0 20444 45646 0.0 37.5 8.0 20447 44238 0.0 37.5 8.0 20448 44936 0.0 50.0 8.0 20451 44161 0.0 37.5 8.0 20459 44938 0.0 50.0 8.0 20460 45636 0.0 50.0 8.0 20467 44804 0.0 37.5 8.0 20473 44100 0.0 50.0 8.0 20534 46230 0.0 37.5 8.0 20537 45532 0.0 37.5 8.0 20547 45526 0.0 50.0 8.0 20563 45536 0.0 37.5 8.0 20583 41535 0.0 42.9 7.0 20584 40123 0.0 57.1 7.0 20590 41525 0.0 42.9 7.0 20601 40817 0.0 42.9 7.0 20610 40821 0.0 42.9 7.0 20619 41529 0.0 42.9 7.0 20622 40825 0.0 42.9 7.0 20635 41527 0.0 42.9 7.0 20686 41527 0.0 42.9 7.0 20708 40823 0.0 42.9 7.0 20717 38758 0.0 57.1 7.0 20719 42229 0.0 42.9 7.0 20733 38764 0.0 42.9 7.0 20744 42235 0.0 42.9 7.0 20758 42239 0.0 42.9 7.0 20825 39472 0.0 42.9 7.0 20912 40868 0.0 57.1 7.0 20928 40866 0.0 42.9 7.0 20940 41576 0.0 42.9 7.0 20968 40870 0.0 42.9 7.0 21055 39488 0.0 42.9 7.0 21107 40888 0.0 42.9 7.0 21130 40886 0.0 42.9 7.0 21140 40890 0.0 42.9 7.0 21155 41588 0.0 42.9 7.0 21176 41596 0.0 42.9 7.0 21218 42290 0.0 42.9 7.0 21242 43118 0.0 50.0 8.0 21290 43114 0.0 62.5 8.0 21331 45220 0.0 37.5 8.0 21350 44518 0.0 37.5 8.0 21529 43120 0.0 37.5 8.0 21549 43812 0.0 50.0 8.0 21586 43810 0.0 50.0 8.0 21633 45224 0.0 50.0 8.0 21639 45226 0.0 37.5 8.0 21655 45922 0.0 37.5 8.0 21661 43265 0.0 37.5 8.0 21691 42573 0.0 37.5 8.0 21714 45232 0.0 37.5 8.0 21742 41161 0.0 71.4 7.0 21753 41163 0.0 42.9 7.0 21802 44591 0.0 50.0 8.0 21805 43189 0.0 37.5 8.0 21807 45293 0.0 37.5 8.0 21808 42487 0.0 37.5 8.0 21811 43191 0.0 37.5 8.0 21815 38917 0.0 42.9 7.0 21819 38913 0.0 42.9 7.0 21826 41875 0.0 42.9 7.0 21827 45987 0.0 37.5 8.0 21837 45289 0.0 37.5 8.0 21838 45989 0.0 50.0 8.0 21969 44537 0.0 50.0 8.0 16070 44681 12.5 37.5 8.0 16076 43981 12.5 50.0 8.0 16068 44675 37.5 0.0 8.0 16094 42428 37.5 0.0 8.0 19238 45866 37.5 0.0 8.0 17843 39216 42.9 0.0 7.0 18039 41657 42.9 0.0 7.0 21138 40188 42.9 0.0 7.0 16006 44200 50.0 0.0 8.0 19609 43404 50.0 0.0 8.0 16590 42108 57.1 0.0 7.0 20674 40125 57.1 0.0 7.0 17581 44634 62.5 0.0 8.0 17508 46399 71.4 0.0 7.0 17968 38827 71.4 0.0 7.0 16007 44202 75.0 0.0 8.0 17965 41244 85.7 0.0 7.0 16108 43970 87.5 0.0 8.0 16104 43972 100.0 0.0 8.0

Table 137 below provides the data for differential expression analysis on the arrays using samples from metastasized colon tissue. In this example, the samples used for hybridization sequences on the microarray were derived from the matched metastasized (MT) colon tissue and normal (N) colon tissues of the patients. Table 137 includes: 1) the SEQ ID NO: 2) the percentage of patients tested in which expression levels of the gene (as detected using the corresponding clone) was at least 2-fold greater in metastasized cancerous colon tissue (MT) than in matched normal tissue (“Colon>2×MT/N”); 5) the percentage of patients tested in which expression levels of the gene was less than or equal to one-half of the expression level in matched normal cells (“Colon<=half×T/N”); and 8) the colon number ratios, indicating the number of patients upon which the provided ratios was based. The corresponding data with the same sequence of the colon tumor tissue versus matched normal colon tissue (T/N) are provided for convenience in comparison.

TABLE 137 Polynucleotides Corresponding to Differnetially Expressed Genes in Metastasized Colon Cancer Tissue Colon MT/N SEQ Colon Colon MT/N < Num Ratios Colon T/N > Colon T/N < Colon T/N ID NO MT/N > 2x halfx by Clone 2x halfx Num Ratios 16207 40.0 0.0 5.0 0.0 50.0 8.0 16314 0.0 40.0 5.0 0.0 37.5 8.0 17643 0.0 40.0 5.0 0.0 37.5 8.0 17962 40.0 0.0 5.0 0.0 42.9 7.0 18336 20.0 40.0 5.0 0.0 85.7 7.0 18342 20.0 80.0 5.0 0.0 71.4 7.0 18343 20.0 40.0 5.0 0.0 85.7 7.0 18637 0.0 40.0 5.0 0.0 62.5 8.0 21331 0.0 40.0 5.0 0.0 37.5 8.0

Table 138 below provides the data for differential expression analysis on the arrays using samples from matched cancerous and normal prostate tissue (PT/N). Table 138 includes: 1) the SEQ ID NO; 2) the percentage of patients tested in which expression levels of the gene (as detected using the corresponding clone) was at least 2-fold greater in metastasized cancerous prostate tissue (PT) than in matched normal tissue (“Colon>2×PT/N”); 3) the percentage of patients tested in which expression levels of the gene was less than or equal to one-half of the expression level in matched normal cells (“Colon<=half×PT/N”); and 4) the prostate PT/N number ratios, indicating the number of patients upon which the provided ratios was based. The corresponding data with the same sequences for the colon tumor versus normal (T/N) and metastasized colon tissue versus normal (MT/N) are provided for convenience in comparison.

TABLE 138 Polynucleotides Corresponding to Differnetially Expressed Genes in Prostate Cancer Tissue Prostate Colon Prostate Prostate (PT/N) Colon Colon Colon T/N Colon Colon MT/N SEQ (PT/N) > (PT/N) < Num T/N > T/N < Num MT/N > MT/N < Num ID NO 2x halfx Ratios 2x halfx Ratios 2x halfx Ratios 16129 11.1 33.3 9.0 0.0 50.0 8.0 16480 37.5 12.5 8.0 0.0 71.4 7.0 16619 33.3 11.1 9.0 16634 12.5 37.5 8.0 0.0 42.9 7.0 17664 33.3 0.0 9.0 18336 37.5 25.0 8.0 0.0 85.7 7.0 20.0 40.0 5.0 18342 37.5 12.5 8.0 0.0 71.4 7.0 20.0 80.0 5.0 18410 22.2 33.3 9.0 19286 33.3 0.0 9.0 0.0 37.5 8.0

Example 86 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells can be further analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

Methods for analysis using antisense technology are well known in the art. For example, a number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein can be designed as antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of antisense oligomers specific to each candidate target are designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors considered when designing antisense oligonucleotides include: 1) the secondary structure of oligonucleotides; 2) the secondary structure of the target gene; 3) the specificity with no or minimum cross-hybridization to other expressed genes; 4) stability; 5) length and 6) terminal GC content. The antisense oligonucleotide is designed to so that it will hybridize to its target sequence under conditions of high stringency at physiological temperatures (e.g., an optimal temperature for the cells in culture to provide for hybridization in the cell, e.g., about 37° C.), but with minimal formation of homodimers.

Once synthesized and quantitated, the oligomers are screened for efficiency of a transcript knock-out in a panel of cancer cell lines. The efficiency of the knock-out is determined by analyzing mRNA levels using lightcycler quantification. The oligomers that resulted in the highest level of transcript knock-out, wherein the level was at least about 50%, preferably about 80-90%, up to 95% or more up to undetectable message, are selected for use in a cell-based proliferation assay, an anchorage independent growth assay, and an apoptosis assay.

For example, where the polynucleotide is identified as having a role in colon cancer, the ability of the corresponding designed antisense oligonucleotide to inhibit gene expression is tested through transfection into SW620 colon colorectal carcinoma cells. For each transfection mixture, a carrier molecule, preferably a lipitoid or cholesteroid, is prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide is then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide is further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, lipitoid or cholesteroid, typically in the amount of about 1.5-2 nmol lipitoid/μg antisense oligonucleotide, is diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide is immediately added to the diluted lipitoid and mixed by pipetting up and down. Oligonucleotide is added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interest in the transfected cells is quantitated in the cancer cell lines using the Roche LightCycler™ real-time PCR machine. Values for the target mRNA are normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water added to a total volume of 12.5 μl. To each tube 7.5 μl of a buffer/enzyme mixture is added, which is prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents are mixed by pipetting up and down, and the reaction mixture incubated at 42° C. for 1 hour. The contents of each tube are centrifuged prior to amplification.

An amplification mixture is prepared by mixing in the following order: 1×PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT are added, and amplification carried out according to standard protocols.

The results can be expressed as the percent decrease in expression of the corresponding gene product relative to non-transfected cells, vehicle-only transfected (mock-transfected) cells, or cells transfected with reverse control oligonucleotides.

Example 87 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferation can be assessed in, for example, metastatic breast cancer cell lines (MDA-MB-231 (“231”)), SW620 colon colorectal carcinoma cells, or SKOV3 cells (a human ovarian carcinoma cell line).

Cells are plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide is diluted to 2 μM in OptiMEM™ and added to OptiMEM™ into which the delivery vehicle, lipitoid 116-6 in the case of SW620 cells or 1:1 lipitoid 1:cholesteroid 1 in the case of MDA-MB-231 cells, had been diluted. The oligo/delivery vehicle mixture is then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments was 300 nM, and the final ratio of oligo to delivery vehicle for all experiments is 1.5 nmol lipitoid/μg oligonucleotide.

Antisense oligonucleotides are prepared as described above (see Example 86). Cells are transfected overnight at 37° C. and the transfection mixture replaced with fresh medium the next morning. Transfection is carried out as described above in Example 83.

Those antisense oligonucleotides that inhibit proliferation represent genes that play a role in production or maintenance of the cancerous phenotype.

Example 88 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of, for example, SW620 cells, SKOV3 cells, and MD-MBA-231 cells can be tested in a soft agar assay. Soft agar assays are conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer is formed on the bottom layer by removing cells transfected as described above from plates using 0.05% trypsin and washing twice in media. The cells are counted in a Coulter counter, and resuspended to 106 per ml in media. 10 μl aliquots are placed with media in 96-well plates (to check counting with WST1), or diluted further for the soft agar assay. 2000 cells are plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidifies, 2 ml of media is dribbled on top and antisense or reverse control oligo (produced as described in Example 86) added without delivery vehicles. Fresh media and oligos are added every 3-4 days. Colonies usually are expected to form in 10 days to 3 weeks. Fields of colonies are counted by eye. Wst-1 metabolism values can be used to compensate for small differences in starting cell number. Larger fields can be scanned for visual record of differences.

Those antisense oligonucleotides that inhibited colony formation represent genes that play a role in production or maintenance of the cancerous phenotype.

Example 89 Induction of Cell Death Upon Depletion of Polypeptides by Depletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon cell death, SW620 cells, or other cells derived from a cancer of interest, are transfected for proliferation assays. For cytotoxic effect in the presence of cisplatin (cis), the same protocol is followed but cells are left in the presence of 2 μM drug. Each day, cytotoxicity was monitored by measuring the amount of LDH enzyme released in the medium due to membrane damage. The activity of LDH is measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). A positive control using antisense and reverse control oligonucleotides for BCL2 (a known anti-apoptotic gene) is included; loss of message for BCL2 leads to an increase in cell death compared with treatment with the control oligonucleotide (background cytotoxicity due to transfection).

Example 90 Functional Analysis of Gene Products Differentially Expressed in Cancer

The gene products of sequences of a gene differentially expressed in cancerous cells can be further analyzed to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting or inhibiting development of a metastatic phenotype. For example, the function of gene products corresponding to genes identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted or associated with a cell surface membrane, blocking antibodies can be generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype.

Where the gene product of the differentially expressed genes identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecules that inhibit or enhance function of the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limited to, those that analyze the effect of expression of the corresponding gene upon cell cycle and cell migration. Methods for performing such assays are well known in the art.

Example 91 Contig Assembly and Additional Gene Characterization

The sequences of the polynucleotides provided in the present invention can be used to extend the sequence information of the gene to which the polynucleotides correspond (e.g., a gene, or mRNA encoded by the gene, having a sequence of the polynucleotide described herein). This expanded sequence information can in turn be used to further characterize the corresponding gene, which in turn provides additional information about the nature of the gene product (e.g., the normal function of the gene product). The additional information can serve to provide additional evidence of the gene product's use as a therapeutic target, and provide further guidance as to the types of agents that can modulate its activity.

For example, a contig can be assembled using the sequence of a polynucleotide described herein. A “contig” is a contiguous sequence of nucleotides that is assembled from nucleic acid sequences having overlapping (e.g., shared or substantially similar) sequence information. The sequences of publicly-available ESTs (Expressed Sequence Tags) and the sequences of various clones from several cDNA libraries synthesized at Chiron were used in the contig assembly. The contig is assembled using the software program Sequencher, version 4.05, according to the manufacturer's instructions. The resulting contig can then be used to search both the public databases as well as databases internal to the applicants to match the polynucleotide contiged with homology data and/or differential gene expressed data.

The sequence information obtained in the contig assembly described above can be used to obtain a consensus sequence derived from the contig using the Sequencher program. The consensus sequence can then be used as a query sequence in a BLASTN search of the DGTI DoubleTwist Gene Index (DoubleTwist, Inc., Oakland, Calif.), which contains all the EST and non-redundant sequence in public databases. Alternatively, a sequence of a polynucleotide described herein can be used directly as a query sequence in a BLASTN search of the DGTI DoubleTwist Gene Index.

Through contig assembly and the use of homology searching software programs, the sequence information provided herein can be readily extended to confirm, or confirm a predicted, gene having the sequence of the polynucleotides described in the present invention. Further the information obtained can be used to identify the function of the gene product of the gene corresponding to the polynucleotides described herein. While not necessary to the practice of the invention, identification of the function of the corresponding gene, can provide guidance in the design of therapeutics that target the gene to modulate its activity and modulate the cancerous phenotype (e.g., inhibit metastasis, proliferation, and the like).

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

Deposit Information.

A deposit of the biological materials in the tables referenced below was made with the American Type Culture Collection, 10801 University Blvd., Manasas, Va. 20110-2209, under the provisions of the Budapest Treaty, on or before the filing date of the present application. The accession number indicated is assigned after successful viability testing, and the requisite fees were paid. Access to said cultures will be available during pendency of the patent application to one determined by the Commissioner to be entitled to such under 37 C.F.R. §1.14 and 35 U.S.C. §122. All restriction on availability of said cultures to the public will be irrevocably removed upon the granting of a patent based upon the application. Moreover, the designated deposits will be maintained for a period of thirty (30) years from the date of deposit, or for five (5) years after the last request for the deposit; or for the enforceable life of the U.S. patent, whichever is longer. Should a culture become nonviable or be inadvertently destroyed, or, in the case of plasmid-containing strains, lose its plasmid, it will be replaced with a viable culture(s) of the same taxonomic description.

These deposits are provided merely as a convenience to those of skill in the art, and are not an admission that a deposit is required. A license may be required to make, use, or sell the deposited materials, and no such license is hereby granted. The deposit below was received by the ATCC on or before the filing date of the present application.

TABLE 139 Cell Lines Deposited with ATCC ATCC CMCC Cell Line Deposit Date Accession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB- May 15, 1998 CRL-12532 10583 231 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containing specific clones, were assigned an “ES” number (internal reference) and deposited with the ATCC. Table 141 below provides the ATCC Accession Nos. of the ES deposits, all of which were deposited on or before Jun. 13, 2000.

TABLE 140 Pools of Clones and Libraries Deposited with ATCC on or before Jun. 13, 2000. Library No. CMCC No. ATCC Accession No. ES 168 5276 PTA-2027 ES 169 5277 PTA-2028 ES 170 5284 PTA-2029 ES 171 5285 PTA-2030 ES 172 5286 PTA-2031 ES 173 5287 PTA-2032 ES 174 5288 PTA-2033 ES 175 5289 PTA-2034 ES 176 5290 PTA-2035 ES 177 5291 PTA-2036 ES 178 5292 PTA-2037 ES 179 5293 PTA-2038 ES 180 5294 PTA-2039 ES 181 5295 PTA-2040 ES 182 5296 PTA-2041 ES 183 5297 PTA-2042 ES 184 5298 PTA-2043 ES 185 5299 PTA-2044 ES 186 5301 PTA-2045 ES 187 5302 PTA-2046 ES 188 5303 PTA-2047 ES 189 5304 PTA-2052 ES 190 5305 PTA-2053 ES 191 5306 PTA-2054 ES 192 5307 PTA-2055 ES 193 5308 PTA-2056 ES 194 5309 PTA-2057 ES 195 5310 PTA-2058 ES 196 5311 PTA-2059 ES 197 5312 PTA-2060 ES 198 5313 PTA-2061 ES 199 5314 PTA-2062 ES 200 5315 PTA-2048 ES 201 5316 PTA-2049 ES 202 5317 PTA-2063 ES 203 5318 PTA-2064 ES 204 5319 PTA-2065 ES 205 5320 PTA-2066 ES 206 5321 PTA-2067 ES 207 5322 PTA-2068 ES 208 5253 PTA-2050 ES 209 5324 PTA-2051

Table 141 (inserted before the claims) provides the clones in each of the above libraries.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where the ATCC deposit is composed of a pool of cDNA clones or a library of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones in the pool or library were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

Example 92 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

Candidate polynucleotides that may represent novel polynucleotides were obtained from cDNA libraries generated from selected cell lines and patient tissues. In order to obtain the candidate polynucleotides, mRNA was isolated from several selected cell lines and patient tissues, and used to construct cDNA libraries. The cells and tissues that served as sources for these cDNA libraries are summarized in Table 142 below.

Human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863) is derived from the KM12C cell line. The KM12C cell line (Morikawa et al. Cancer Res. (1988) 48:1943-1948), which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B2 surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KM12L4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246).

The MDA-MB-231 cell line (Brinkley et al. Cancer Res. (1980) 40:3118-3129) was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)).

The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation.

GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

The source materials for generating the normalized prostate libraries of libraries 25 and 26 were cryopreserved prostate tumor tissue from a patient with Gleason grade 3+3 adenocarcinoma and matched normal prostate biopsies from a pool of at-risk subjects under medical surveillance. The source materials for generating the normalized prostate libraries of libraries 30 and 31 were cryopreserved prostate tumor tissue from a patient with Gleason grade 4+4 adenocarcinoma and matched normal prostate biopsies from a pool of at-risk subjects under medical surveillance.

The source materials for generating the normalized breast libraries of libraries 27, 28 and 29 were cryopreserved breast tissue from a primary breast tumor (infiltrating ductal carcinoma)(library 28), from a lymph node metastasis (library 29), or matched normal breast biopsies from a pool of at-risk subjects under medical surveillance. In each case, prostate or breast epithelia were harvested directly from frozen sections of tissue by laser capture microdissection (LCM, Arcturus Enginering Inc., Mountain View, Calif.), carried out according to methods well known in the art (see, Simone et al. Am J Pathol. 156(2):445-52 (2000)), to provide substantially homogenous cell samples.

TABLE 142 Description of cDNA Libraries Number Library of Clones (lib#) Description in Library 0 Artificial library composed of deselected clones (clones with no 673 associated variant or cluster) 1 Human Colon Cell Line Km12 L4: High Metastatic Potential 308731 (derived from Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic Potential 284771 3 Human Breast Cancer Cell Line MDA-MB-231: High Metastatic 326937 Potential; micro-mets in lung 4 Human Breast Cancer Cell Line MCF7: Non Metastatic 318979 8 Human Lung Cancer Cell Line MV-522: High Metastatic Potential 223620 9 Human Lung Cancer Cell Line UCP-3: Low Metastatic Potential 312503 12 Human microvascular endothelial cells (HMEC) - UNTREATED 41938 (PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells (HMEC) - bFGF TREATED 42100 (PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells (HMEC) - VEGF TREATED 42825 (PCR (OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTED PCR (OligodT) 282722 cDNA library) 16 Colon Tumor - UC#2 Patient (MICRODISSECTED PCR (OligodT) 298831 cDNA library) 17 Liver Metastasis from Colon Tumor of UC#2 Patient 303467 (MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED PCR (OligodT) 36216 cDNA library) 19 Colon Tumor - UC#3 Patient (MICRODISSECTED PCR (OligodT) 41388 cDNA library) 20 Liver Metastasis from Colon Tumor of UC#3 Patient 30956 (MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived from normal prostate epithelium 164801 22 WOca Cells derived from Gleason Grade 4 prostate cancer 162088 epithelium 23 Normal Lung Epithelium of Patient #1006 (MICRODISSECTED 306198 PCR (OligodT) cDNA library) 24 Primary tumor, Large Cell Carcinoma of Patient #1006 309349 (MICRODISSECTED PCR (OligodT) cDNA library) 25 Normal Prostate Epithelium from Patient IF97-26811 279444 26 Prostate Cancer Epithelium Gleason 3 + 3 Patient IF97-26811 269406 27 Normal Breast Epithelium from Patient 515 239494 28 Primary Breast tumor from Patient 515 259960 29 Lymph node metastasis from Patient 515 326786 30 Normal Prostate Epithelium from Chiron Patient ID 884 298431 31 Prostate Cancer Epithelium (Gleason 4 + 4) from Chiron Patient ID 331941 884

Characterization of Sequences in the Libraries

After using the software program Phred (ver 0.000925.c, Green and Weing, ©1993-2000) to select those polynucleotides having the best quality sequence, the polynucleotides were compared against the public databases to identify any homologous sequences. The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the RepeatMasker masking program, publicly available through a web site supported by the University of Washington (See also Smit, A. F. A. and Green, P., unpublished results). Generally, masking does not influence the final search results, except to eliminate sequences of relatively little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats.

The remaining sequences were then used in a homology search of the GenBank database using the TeraBLAST program (TimeLogic, Crystal Bay, Nev.). TeraBLAST is a version of the publicly available BLAST search algorithm developed by the National Center for Biotechnology, modified to operate at an accelerated speed with increased sensitivity on a specialized computer hardware platform. The program was run with the default parameters recommended by TimeLogic to provide the best sensitivity and speed for searching DNA and protein sequences. Sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10e-40 were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a TeraBLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the GenBank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10e-5), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10e-5). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10e-40 were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a TeraBLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10e-40 were discarded. Sequences with a p value of less than 1×10e-65 when compared to a database sequence of human origin were also excluded. Second, a TeraBLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p value less than 1×10e-40, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10e-111 in relation to a database sequence of human origin were specifically excluded. The final result provided the sequences listed as SEQ ID NOS:22001-23267 in the accompanying Sequence Listing and summarized in Table 143 (inserted prior to claims). Each identified polynucleotide represents sequence from at least a partial mRNA transcript.

Summary of Polynucleotides of the Invention

Table 143 (inserted prior to claims) provides a summary of polynucleotides isolated as described. Specifically, Table 143 provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for use in the present specification; 2) the Cluster Identification No. (“CLUSTER”); 3) the Sequence Name assigned to each sequence; 3) the sequence name (“SEQ NAME”) used as an internal identifier of the sequence; 4) the orientation of the sequence (“ORIENT”) (either forward (F) or reverse (R)); 5) the name assigned to the clone from which the sequence was isolated (“CLONE ID”); and 6) the name of the library from which the sequence was isolated (“LIBRARY”). Because at least some of the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides may represent different regions of the same mRNA transcript and the same gene and/or may be contained within the same clone. Thus, for example, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene. Clones which comprise the sequences described herein were deposited as set out in the tables indicated below (see Example entitled “Deposit Information”).

Example 93 Contig Assembly

The sequences of the polynucleotides provided in the present invention can be used to extend the sequence information of the gene to which the polynucleotides correspond (e.g., a gene, or mRNA encoded by the gene, having a sequence of the polynucleotide described herein). This expanded sequence information can in turn be used to further characterize the corresponding gene, which in turn provides additional information about the nature of the gene product (e.g., the normal function of the gene product). The additional information can serve to provide additional evidence of the gene product's use as a therapeutic target, and provide further guidance as to the types of agents that can modulate its activity.

For example, a contig was assembled using the sequence of a polynucleotide described herein. A “contig” is a contiguous sequence of nucleotides that is assembled from nucleic acid sequences having overlapping (e.g., shared or substantially similar) sequence information. The sequences of publicly-available ESTs (Expressed Sequence Tags) and the sequences of various of the above-described polynucleotides were used in the contig assembly. The contig was assembled using the software program Sequencher, version 4.05, according to the manufacturer's instructions. The sequence information obtained in the contig assembly was then used to obtain a consensus sequence derived from the contig using the Sequencher program. The resulting consensus sequence was used to search both the public databases as well as databases internal to the applicants to match the consensus polynucleotide with homology data and/or differential gene expressed data.

The final result provided the sequences listed as SEQ ID NOS: 23268-23385 in the accompanying Sequence Listing and summarized in Table 144 (inserted prior to claims). Table 144 provides a summary of the consensus sequences assembled as described. Specifically, Table 144 provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for use in the present specification; 2) the consensus sequence name (“CONSENSUS SEQ NAME”) used as an internal identifier of the sequence; and 3) the sequence name (“POLYNTD SEQ NAME”) of a polynucleotide of SEQ ID NOS: 22001-23267 used in assembly of the consensus sequence.

TABLE 144 CONSENSUS SEQ ID SEQ NAME POLYNTD SEQ NAME 23268 Clu1009284.1 2490.J22.GZ43_363450 23269 Clu1022935.2 2561.O19.GZ43_376586 23270 Clu1037152.1 2558.L19.GZ43_374594 23271 Clu13903.1 2489.A13.GZ43_362841 23272 Clu139979.2 2504.B21.GZ43_365834 23273 Clu163602.2 2561.H17.GZ43_376416 23274 Clu187860.2 2474.P22.GZ43_361999 23275 Clu189993.1 2505.N19.GZ43_366504 23276 Clu20975.1 2466.F16.GZ43_360217 23277 Clu217122.1 2458.N10.GZ43_356930 23278 Clu218833.1 2562.O01.GZ43_375800 23279 Clu244504.2 2367.E23.GZ43_346113 23280 Clu271456.1 2365.G19.GZ43_345389 23281 Clu376516.1 2457.J23.GZ43_356451 23282 Clu376630.1 2467.B11.GZ43_360500 23283 Clu377044.2 2499.A22.GZ43_365257 23284 Clu379689.1 2540.M18.GZ43_372313 23285 Clu380482.2 2542.D09.GZ43_372856 23286 Clu387530.4 2475.N08.GZ43_362321 23287 Clu388450.2 2497.L05.GZ43_364736 23288 Clu396325.1 2561.P16.GZ43_376607 23289 Clu397115.3 2560.K18.GZ43_375337 23290 Clu398642.2 2542.N22.GZ43_373109 23291 Clu400258.1 2504.O12.GZ43_366137 23292 Clu402167.1 2540.C21.GZ43_372076 23293 Clu402591.3 2483.E11.GZ43_359762 23294 Clu402904.1 2504.J02.GZ43_366007 23295 Clu404081.2 2483.K02.GZ43_359897 23296 Clu411524.1 2497.C11.GZ43_364526 23297 Clu41346.1 2560.K08.GZ43_375327 23298 Clu415520.1 2561.L14.GZ43_376509 23299 Clu416124.1 2367.G17.GZ43_346155 23300 Clu417672.1 2367.I09.GZ43_346195 23301 Clu423664.1 2488.H12.GZ43_362624 23302 Clu429609.1 2457.M11.GZ43_356511 23303 Clu442923.3 2498.G15.GZ43_365010 23304 Clu446975.1 2459.K15.GZ43_357247 23305 Clu449839.2 2497.O09.GZ43_364812 23306 Clu449889.1 2475.N21.GZ43_362334 23307 Clu451707.2 2554.P16.GZ43_376223 23308 Clu454509.3 2542.M09.GZ43_373072 23309 Clu454796.1 2540.P02.GZ43_372369 23310 Clu455862.1 2560.I09.GZ43_375280 23311 Clu460493.1 2483.O07.GZ43_359998 23312 Clu464200.1 2465.G06.GZ43_358214 23313 Clu465446.2 2457.L21.GZ43_356497 23314 Clu470032.1 2474.C01.GZ43_361666 23315 Clu474125.1 2457.E23.GZ43_356331 23316 Clu474125.2 2541.A06.GZ43_372397 23317 Clu477271.1 2540.E17.GZ43_372120 23318 Clu480410.1 2498.H08.GZ43_365027 23319 Clu483211.2 2510.J18.GZ43_369259 23320 Clu497138.1 2458.N19.GZ43_356939 23321 Clu498886.1 2465.L22.GZ43_358350 23322 Clu498886.2 2541.B15.GZ43_372430 23323 Clu5013.2 2559.D05.GZ43_374772 23324 Clu5105.2 2542.D19.GZ43_372866 23325 Clu510539.2 2558.H17.GZ43_374496 23326 Clu514044.1 2367.F13.GZ43_346127 23327 Clu516526.1 2456.F23.GZ43_355971 23328 Clu519176.2 2559.H20.GZ43_374883 23329 Clu520370.1 2541.N01.GZ43_372704 23330 Clu524917.1 2464.H05.GZ43_357853 23331 Clu528957.1 2540.F15.GZ43_372142 23332 Clu533888.1 2557.L23.GZ43_374214 23333 Clu534076.1 2456.C05.GZ43_355881 23334 Clu540142.2 2456.H02.GZ43_355998 23335 Clu540379.2 2491.O02.GZ43_363934 23336 Clu549507.1 2483.B23.GZ43_359702 23337 Clu551338.3 2457.I12.GZ43_356416 23338 Clu552537.2 2540.C10.GZ43_372065 23339 Clu556827.3 2558.E24.GZ43_374431 23340 Clu558569.2 2558.D03.GZ43_374386 23341 Clu565709.1 2542.P02.GZ43_373137 23342 Clu568204.1 2456.M05.GZ43_356121 23343 Clu570804.1 2475.M20.GZ43_362309 23344 Clu572170.2 2557.H03.GZ43_374098 23345 Clu573764.1 2365.C10.GZ43_345284 23346 Clu587168.1 2483.F15.GZ43_359790 23347 Clu588996.1 2466.G06.GZ43_360231 23348 Clu597681.1 2459.A04.GZ43_356996 23349 Clu598388.1 2562.E03.GZ43_375562 23350 Clu604822.2 2504.F20.GZ43_365929 23351 Clu621573.1 2535.A08.GZ43_370095 23352 Clu625055.1 2511.A07.GZ43_369416 23353 Clu627263.1 2466.D20.GZ43_360173 23354 Clu635332.1 2480.D13.GZ43_358588 23355 Clu640911.2 2541.M24.GZ43_372703 23356 Clu641662.2 2555.D22.GZ43_373253 23357 Clu659483.1 2365.F12.GZ43_345358 23358 Clu6712.1 2535.P14.GZ43_370461 23359 Clu676448.3 2464.B01.GZ43_357705 23360 Clu682065.2 2467.E19.GZ43_360580 23361 Clu685244.2 2561.J01.GZ43_376448 23362 Clu691653.1 2560.O12.GZ43_375427 23363 Clu692282.1 2561.I11.GZ43_376434 23364 Clu697955.1 2557.J22.GZ43_374165 23365 Clu702885.3 2555.H18.GZ43_373345 23366 Clu70908.1 2561.C15.GZ43_376294 23367 Clu709796.2 2542.C20.GZ43_372843 23368 Clu715752.1 2459.A24.GZ43_357016 23369 Clu727966.1 2489.F09.GZ43_362957 23370 Clu732950.2 2475.L17.GZ43_362282 23371 Clu752623.2 2561.I07.GZ43_376430 23372 Clu756337.1 2561.I19.GZ43_376442 23373 Clu782981.1 2489.L05.GZ43_363097 23374 Clu805118.3 2480.D16.GZ43_358591 23375 Clu806992.2 2467.D20.GZ43_360557 23376 Clu823296.3 2558.P20.GZ43_374691 23377 Clu830453.2 2540.M22.GZ43_372317 23378 Clu839006.1 2507.H02.GZ43_367111 23379 Clu847088.1 2542.H23.GZ43_372966 23380 Clu853371.2 2491.I06.GZ43_363794 23381 Clu88462.1 2510.K15.GZ43_369280 23382 Clu935908.2 2505.O09.GZ43_366518 23383 Clu948383.1 2541.F05.GZ43_372516 23384 Clu966599.3 2507.L12.GZ43_367217 23385 Clu993554.1 2558.F19.GZ43_374450

Example 94 Additional Gene Characterization

Sequences of the polynucleotides of SEQ ID NOS: 22001-23267 were used as a query sequence in a TeraBLASTN search of the DoubleTwist Human Genome Sequence Database (DoubleTwist, Inc., Oakland, Calif.), which contains all the human genomic sequences that have been assembled into a contiguous model of the human genome. Predicted cDNA and protein sequences were obtained where a polynucleotide of the invention was homologous to a predicted full-length gene sequence. Alternatively, a sequence of a contig or consensus sequence described herein could be used directly as a query sequence in a TeraBLASTN search of the DoubleTwist Human Genome Sequence Database.

The final results of the search provided the predicted cDNA sequences listed as SEQ ID NOS: 1386-1477 in the accompanying Sequence Listing and summarized in Table 145 (inserted prior to claims), and the predicted protein sequences listed as SEQ ID NOS:23478-23568 in the accompanying Sequence Listing and summarized in Table 146 (inserted prior to claims). Specifically, Table 145 provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each cDNA sequence for use in the present specification; 2) the cDNA sequence name (“cDNA SEQ NAME”) used as an internal identifier of the sequence; 3) the sequence name (“POLYNTD SEQ NAME”) of the polynucleotide of SEQ ID NO that maps to the cDNA; 4) The gene id number (GENE) of the DoubleTwist predicted gene; 5) the chromosome (“CHROM”) containing the gene corresponding to the cDNA sequence; Table 146 provides: 1) the SEQ ID NO (“SEQ ID”) assigned to each protein sequence for use in the present specification; 2) the protein sequence name (“PROTEIN SEQ NAME”) used as an internal identifier of the sequence; 3) the sequence name (“POLYNTD SEQ NAME”) of the polynucleotide of SEQ ID NOS: 22001-23267 that maps to the protein sequence; 4) The gene id number (GENE) of the DoubleTwist predicted gene; 5) the chromosome (“CHROM”) containing the gene corresponding to the cDNA sequence.

TABLE 145 cDNA SEQ POLYNTD SEQ SEQ ID NAME NAME GENE CHROM 23386 DTT00087024.1 2467.H18.GZ43_360651 DTG00087008.1 1 23387 DTT00089020.1 2367.I15.GZ43_346201 DTG00089002.1 1 23388 DTT00171014.1 2473.F14.GZ43_361367 DTG00171001.1 1 23389 DTT00514029.1 2488.G02.GZ43_362590 DTG00514005.1 1 23390 DTT00740010.1 2466.I08.GZ43_360281 DTG00740003.1 1 23391 DTT00945030.1 2466.D19.GZ43_360172 DTG00945008.1 1 23392 DTT01169022.1 2464.N05.GZ43_357997 DTG01169003.1 2 23393 DTT01178009.1 2510.O21.GZ43_369382 DTG01178002.1 2 23394 DTT01315010.1 2496.F14.GZ43_364217 DTG01315001.1 2 23395 DTT01503016.1 2538.M17.GZ43_371544 DTG01503005.1 2 23396 DTT01555018.1 2538.C07.GZ43_371294 DTG01555002.1 2 23397 DTT01685047.1 2496.C08.GZ43_364139 DTG01685007.1 2 23398 DTT01764019.1 2535.C23.GZ43_370158 DTG01764003.1 2 23399 DTT01890015.1 2482.J06.GZ43_359493 DTG01890004.1 2 23400 DTT02243008.1 2474.J19.GZ43_361852 DTG02243002.1 3 23401 DTT02367007.1 2366.P08.GZ43_345738 DTG02367002.1 3 23402 DTT02671007.1 2464.H22.GZ43_357870 DTG02671002.1 3 23403 DTT02737017.1 2538.M16.GZ43_371543 DTG02737001.1 3 23404 DTT02850005.1 2472.G03.GZ43_360996 DTG02850001.1 3 23405 DTT02966016.1 2510.M14.GZ43_369327 DTG02966003.1 4 23406 DTT03037029.1 2504.D16.GZ43_365877 DTG03037005.1 4 23407 DTT03150008.1 2491.P10.GZ43_363966 DTG03150002.1 4 23408 DTT03367008.1 2542.P19.GZ43_373154 DTG03367003.1 4 23409 DTT03630013.1 2510.O22.GZ43_369383 DTG03630002.1 4 23410 DTT03881017.1 2507.O12.GZ43_367289 DTG03881007.1 5 23411 DTT03913023.1 2459.P24.GZ43_357376 DTG03913005.1 5 23412 DTT03978010.1 2367.G22.GZ43_346160 DTG03978001.1 5 23413 DTT04070014.1 2540.H07.GZ43_372182 DTG04070007.1 5 23414 DTT04084010.1 2542.D19.GZ43_372866 DTG04084001.1 5 23415 DTT04160007.1 2472.M22.GZ43_361159 DTG04160003.1 5 23416 DTT04302021.1 2483.O07.GZ43_359998 DTG04302002.1 5 23417 DTT04378009.1 2368.O11.GZ43_346725 DTG04378001.1 5 23418 DTT04403013.1 2506.M05.GZ43_366850 DTG04403003.1 5 23419 DTT04414015.1 2368.D20.GZ43_346470 DTG04414005.1 5 23420 DTT04660017.1 2507.C03.GZ43_366992 DTG04660003.1 6 23421 DTT04956054.1 2538.I17.GZ43_371448 DTG04956020.1 6 23422 DTT04970018.1 2365.F24.GZ43_345370 DTG04970007.1 6 23423 DTT05205007.1 2459.J12.GZ43_357220 DTG05205001.1 6 23424 DTT05571010.1 2555.J10.GZ43_373385 DTG05571004.1 7 23425 DTT05650008.1 2557.L01.GZ43_374192 DTG05650003.1 7 23426 DTT05742029.1 2560.K10.GZ43_375329 DTG05742002.1 7 23427 DTT06137030.1 2565.B15.GZ43_398171 DTG06137001.1 8 23428 DTT06161014.1 2367.F06.GZ43_346120 DTG06161007.1 8 23429 DTT06706019.1 2467.D10.GZ43_360547 DTG06706003.1 9 23430 DTT06837021.1 2540.I10.GZ43_372209 DTG06837002.1 9 23431 DTT07040015.1 2504.E23.GZ43_365908 DTG07040006.1 9 23432 DTT07088009.1 2565.H01.GZ43_397953 DTG07088001.1 9 23433 DTT07182014.1 2536.G22.GZ43_370637 DTG07182006.0 10 23434 DTT07405044.1 2560.B11.GZ43_375114 DTG07405010.1 10 23435 DTT07408020.1 2466.M02.GZ43_360371 DTG07408005.1 10 23436 DTT07498014.1 2506.K20.GZ43_366817 DTG07498002.1 10 23437 DTT07600010.1 2464.H17.GZ43_357865 DTG07600001.1 10 23438 DTT08005024.1 2475.N21.GZ43_362334 DTG08005009.1 11 23439 DTT08098020.1 2540.M18.GZ43_372313 DTG08098001.1 11 23440 DTT08167018.1 2542.F05.GZ43_372900 DTG08167002.1 11 23441 DTT08249022.1 2498.G15.GZ43_365010 DTG08249008.1 11 23442 DTT08499022.1 2540.A24.GZ43_372031 DTG08499009.1 12 23443 DTT08514022.1 2541.L12.GZ43_372667 DTG08514006.1 12 23444 DTT08527013.1 2489.F09.GZ43_362957 DTG08527005.1 12 23445 DTT08595020.1 2554.N09.GZ43_376168 DTG08595003.1 12 23446 DTT08711019.1 2540.C19.GZ43_372074 DTG08711001.1 12 23447 DTT08773020.1 2559.I12.GZ43_374899 DTG08773008.1 12 23448 DTT08874012.1 2537.P14.GZ43_371229 DTG08874001.1 12 23449 DTT09387018.1 2561.P19.GZ43_376610 DTG09387001.1 14 23450 DTT09396022.1 2489.M11.GZ43_363127 DTG09396001.1 14 23451 DTT09553027.1 2505.J22.GZ43_366411 DTG09553007.1 14 23452 DTT09604016.1 2483.J07.GZ43_359878 DTG09604006.1 14 23453 DTT09705033.1 2536.O22.GZ43_370829 DTG09705006.1 14 23454 DTT09742009.1 2542.N21.GZ43_373108 DTG09742002.1 15 23455 DTT09753017.1 2464.L02.GZ43_357946 DTG09753002.1 15 23456 DTT09793019.1 2464.I04.GZ43_357876 DTG09793004.1 15 23457 DTT09796028.1 2366.L21.GZ43_345942 DTG09796002.1 15 23458 DTT10221016.1 2556.C19.GZ43_373610 DTG10221004.1 16 23459 DTT10360040.1 2475.M20.GZ43_362309 DTG10360016.1 16 23460 DTT10539016.1 2506.J20.GZ43_366793 DTG10539005.1 17 23461 DTT10564022.1 2475.H06.GZ43_362175 DTG10564006.1 17 23462 DTT10683041.1 2542.K21.GZ43_373036 DTG10683007.1 17 23463 DTT10819011.1 2474.I06.GZ43_361815 DTG10819003.1 17 23464 DTT11363027.1 2542.C20.GZ43_372843 DTG11363008.1 19 23465 DTT11479018.1 2506.G24.GZ43_366725 DTG11479007.1 19 23466 DTT11483012.1 2459.H09.GZ43_357169 DTG11483001.1 19 23467 DTT11548015.1 2565.C17.GZ43_398204 DTG11548002.1 19 23468 DTT11730017.1 2535.B09.GZ43_370120 DTG11730004.1 20 23469 DTT11791010.1 2506.E12.GZ43_366665 DTG11791003.1 20 23470 DTT11864036.1 2456.H07.GZ43_356003 DTG11864011.1 21 23471 DTT11902028.1 2490.B06.GZ43_363242 DTG11902009.1 21 23472 DTT11915017.1 2474.G17.GZ43_361778 DTG11915002.1 21 23473 DTT11966040.1 2457.L21.GZ43_356497 DTG11966014.1 22 23474 DTT12042027.1 2459.G01.GZ43_357137 DTG12042005.1 22 23475 DTT12201062.1 2562.B09.GZ43_375496 DTG12201018.1 X 23476 DTT12470020.1 2489.A13.GZ43_362841 DTG12470004.1 X 23477 DTT12550009.1 2504.G01.GZ43_365934 DTG12550003.1 X

TABLE 146 SEQ PROTEIN POLYNTD SEQ DBL TWIST ID SEQ NAME NAME GENE CHROM LOCUS ID 23478 DTP00087033.1 2467.H18.GZ43_360651 DTG00087008.1 1 DTL00087012.1 23479 DTP00089029.1 2367.I15.GZ43_346201 DTG00089002.1 1 DTL00089002.1 23480 DTP00171023.1 2473.F14.GZ43_361367 DTG00171001.1 1 DTL00171013.1 23481 DTP00514038.1 2488.G02.GZ43_362590 DTG00514005.1 1 DTL00514023.1 23482 DTP00740019.1 2466.I08.GZ43_360281 DTG00740003.1 1 DTL00740006.1 23483 DTP00945039.1 2466.D19.GZ43_360172 DTG00945008.1 1 23484 DTP01169031.1 2464.N05.GZ43_357997 DTG01169003.1 2 DTL01169014.1 23485 DTP01178018.1 2510.O21.GZ43_369382 DTG01178002.1 2 DTL01178007.1 23486 DTP01315019.1 2496.F14.GZ43_364217 DTG01315001.1 2 DTL01315004.1 23487 DTP01503025.1 2538.M17.GZ43_371544 DTG01503005.1 2 DTL01503007.1 23488 DTP01555027.1 2538.C07.GZ43_371294 DTG01555002.1 2 DTL01555003.1 23489 DTP01685056.1 2496.C08.GZ43_364139 DTG01685007.1 2 DTL01685004.1 23490 DTP01764028.1 2535.C23.GZ43_370158 DTG01764003.1 2 DTL01764005.1 23491 DTP01890024.1 2482.J06.GZ43_359493 DTG01890004.1 2 DTL01890001.1 23492 DTP02243017.1 2474.J19.GZ43_361852 DTG02243002.1 3 DTL02243002.1 23493 DTP02367016.1 2366.P08.GZ43_345738 DTG02367002.1 3 DTL02367004.1 23494 DTP02671016.1 2464.H22.GZ43_357870 DTG02671002.1 3 DTL02671002.1 23495 DTP02737026.1 2538.M16.GZ43_371543 DTG02737001.1 3 DTL02737012.1 23496 DTP02850014.1 2472.G03.GZ43_360996 DTG02850001.1 3 DTL02850004.1 23497 DTP02966025.1 2510.M14.GZ43_369327 DTG02966003.1 4 DTL02966001.1 23498 DTP03037038.1 2504.D16.GZ43_365877 DTG03037005.1 4 DTL03030074.1 23499 DTP03150017.1 2491.P10.GZ43_363966 DTG03150002.1 4 DTL03149001.1 23500 DTP03367017.1 2542.P19.GZ43_373154 DTG03367003.1 4 DTL03367005.1 23501 DTP03630022.1 2510.O22.GZ43_369383 DTG03630002.1 4 DTL03630006.1 23502 DTP03881026.1 2507.O12.GZ43_367289 DTG03881007.1 5 DTL03881006.1 23503 DTP03913032.1 2459.P24.GZ43_357376 DTG03913005.1 5 DTL03913012.1 23504 DTP03978019.1 2367.G22.GZ43_346160 DTG03978001.1 5 DTL03978003.1 23505 DTP04070023.1 2540.H07.GZ43_372182 DTG04070007.1 5 23506 DTP04084019.1 2542.D19.GZ43_372866 DTG04084001.1 5 DTL04084001.1 23507 DTP04160016.1 2472.M22.GZ43_361159 DTG04160003.1 5 DTL04160003.1 23508 DTP04302030.1 2483.O07.GZ43_359998 DTG04302002.1 5 DTL04302006.1 23509 DTP04378018.1 2368.O11.GZ43_346725 DTG04378001.1 5 23510 DTP04403022.1 2506.M05.GZ43_366850 DTG04403003.1 5 DTL04403004.1 23511 DTP04414024.1 2368.D20.GZ43_346470 DTG04414005.1 5 DTL04414004.1 23512 DTP04660026.1 2507.C03.GZ43_366992 DTG04660003.1 6 DTL04660002.1 23513 DTP04956063.1 2538.I17.GZ43_371448 DTG04956020.1 6 DTL04956028.1 23514 DTP04970027.1 2365.F24.GZ43_345370 DTG04970007.1 6 DTL04970008.1 23515 DTP05205016.1 2459.J12.GZ43_357220 DTG05205001.1 6 DTL05205002.1 23516 DTP05571019.1 2555.J10.GZ43_373385 DTG05571004.1 7 DTL05571003.1 23517 DTP05650017.1 2557.L01.GZ43_374192 DTG05650003.1 7 DTL05650004.1 23518 DTP05742038.1 2560.K10.GZ43_375329 DTG05742002.1 7 DTL05742003.1 23519 DTP06137039.1 2565.B15.GZ43_398171 DTG06137001.1 8 DTL06137003.1 23520 DTP06161023.1 2367.F06.GZ43_346120 DTG06161007.1 8 DTL06161006.1 23521 DTP06706028.1 2467.D10.GZ43_360547 DTG06706003.1 9 DTL06705001.1 23522 DTP06837030.1 2540.I10.GZ43_372209 DTG06837002.1 9 DTL06837010.1 23523 DTP07040024.1 2504.E23.GZ43_365908 DTG07040006.1 9 DTL07040004.1 23524 DTP07088018.1 2565.H01.GZ43_397953 DTG07088001.1. 9 DTL07088004.1 23525 DTP07405053.1 2560.B11.GZ43_375114 DTG07405010.1 10 DTL07405034.1 23526 DTP07408029.1 2466.M02.GZ43_360371 DTG07408005.1 10 DTL07408005.1 23527 DTP07498023.1 2506.K20.GZ43_366817 DTG07498002.1 10 DTL07498007.1 23528 DTP07600019.1 2464.H17.GZ43_357865 DTG07600001.1 10 DTL07600004.1 23529 DTP08005033.1 2475.N21.GZ43_362334 DTG08005009.1 11 DTL08005010.1 23530 DTP08098029.1 2540.M18.GZ43_372313 DTG08098001.1 11 DTL08098013.1 23531 DTP08167027.1 2542.F05.GZ43_372900 DTG08167002.1 11 DTL08167003.1 23532 DTP08249031.1 2498.G15.GZ43_365010 DTG08249008.1 11 DTL08249005.1 23533 DTP08499031.1 2540.A24.GZ43_372031 DTG08499009.1 12 DTL08499012.1 23534 DTP08514031.1 2541.L12.GZ43_372667 DTG08514006.1 12 DTL08514015.1 23535 DTP08527022.1 2489.F09.GZ43_362957 DTG08527005.1 12 DTL08527008.1 23536 DTP08595029.1 2554.N09.GZ43_376168 DTG08595003.1 12 DTL08595002.1 23537 DTP08711028.1 2540.C19.GZ43_372074 DTG08711001.1 12 DTL08710003.1 23538 DTP08773029.1 2559.I12.GZ43_374899 DTG08773008.1 12 DTL08773011.1 23539 DTP08874021.1 2537.P14.GZ43_371229 DTG08874001.1 12 DTL08874009.1 23540 DTP09387027.1 2561.P19.GZ43_376610 DTG09387001.1 14 DTL09387002.1 23541 DTP09396031.1 2489.M11.GZ43_363127 DTG09396001.1 14 DTL09396016.1 23542 DTP09553036.1 2505.J22.GZ43_366411 DTG09553007.1 14 DTL09553018.1 23543 DTP09604025.1 2483.J07.GZ43_359878 DTG09604006.1 14 DTL09604010.1 23544 DTP09705042.1 2536.O22.GZ43_370829 DTG09705006.1 14 DTL09705005.1 23545 DTP09742018.1 2542.N21.GZ43_373108 DTG09742002.1 15 DTL09742007.1 23546 DTP09753026.1 2464.L02.GZ43_357946 DTG09753002.1 15 DTL09753011.1 23547 DTP09793028.1 2464.I04.GZ43_357876 DTG09793004.1 15 DTL09793004.1 23548 DTP09796037.1 2366.L21.GZ43_345942 DTG09796002.1 15 DTL09796021.1 23549 DTP10221025.1 2556.C19.GZ43_373610 DTG10221004.1 16 DTL10221002.1 23550 DTP10360049.1 2475.M20.GZ43_362309 DTG10360016.1 16 DTL10360003.1 23551 DTP10539025.1 2506.J20.GZ43_366793 DTG10539005.1 17 DTL10539004.1 23552 DTP10564031.1 2475.H06.GZ43_362175 DTG10564006.1 17 DTL10564006.1 23553 DTP10683050.1 2542.K21.GZ43_373036 DTG10683007.1 17 DTL10683002.1 23554 DTP10819020.1 2474.106.GZ43_361815 DTG10819003.1 17 DTL10819002.1 23555 DTP11363036.1 2542.C20.GZ43_372843 DTG11363008.1 19 DTL11363017.1 23556 DTP11479027.1 2506.G24.GZ43_366725 DTG11479007.1 19 DTL11479006.1 23557 DTP11483021.1 2459.H09.GZ43_357169 DTG11483001.1 19 DTL11483006.1 23558 DTP11548024.1 2565.C17.GZ43_398204 DTG11548002.1 19 DTL11548003.1 23559 DTP11730026.1 2535.B09.GZ43_370120 DTG11730004.1 20 DTL11730009.1 23560 DTP11791019.1 2506.E12.GZ43_366665 DTG11791003.1 20 DTL11791005.1 23561 DTP11864045.1 2456.H07.GZ43_356003 DTG11864011.1 21 DTL11864023.1 23562 DTP11902037.1 2490.B06.GZ43_363242 DTG11902009.1 21 DTL11902002.1 23563 DTP11915026.1 2474.G17.GZ43_361778 DTG11915002.1 21 DTL11915001.1 23564 DTP11966049.1 2457.L21.GZ43_356497 DTG11966014.1 22 DTL11966006.1 23565 DTP12042036.1 2459.G01.GZ43_357137 DTG12042005.1 22 DTL12042001.1 23566 DTP12201071.1 2562.B09.GZ43_375496 DTG12201018.1 X DTL12201023.1 23567 DTP12470029.1 2489.A13.GZ43_3612841 DTG12470004.1 X DTL12470016.1 23568 DTP12550018.1 2504.G01.GZ43_365934 DTG12550003.1 X DTL12550005.1

A correlation between the polynucleotide used as a query sequence as described above and the corresponding predicted cDNA and protein sequences is contained in Table 147. Specifically Table 147 provides: 1) the SEQ ID NO of the cDNA (“cDNA SEQ ID”); 2) the cDNA sequence name (“cDNA SEQ NAME”) used as an internal identifier of the sequence; 3) the SEQ ID NO of the protein (“PROTEIN SEQ ID”) encoded by the cDNA sequence 4) the sequence name of the protein (“PROTEIN SEQ NAME”) encoded by the cDNA sequence; 5) the SEQ ID NO of the polynucleotide (“POLYNTD SEQ ID”) of SEQ ID NOS: 22001-23267 that maps to the cDNA and protein; and 6) the sequence name (“POLYNTD SEQ NAME”) of the polynucleotide of SEQ ID NOS: 22001-23267 that maps to the cDNA and protein.

Through contig and consensus sequence assembly and the use of homology searching software programs, the sequence information provided herein can be readily extended to confirm, or confirm a predicted, gene having the sequence of the polynucleotides described in the present invention. Further the information obtained can be used to identify the function of the gene product of the gene corresponding to the polynucleotides described herein. While not necessary to the practice of the invention, identification of the function of the corresponding gene, can provide guidance in the design of therapeutics that target the gene to modulate its activity and modulate the cancerous phenotype (e.g., inhibit metastasis, proliferation, and the like).

Example 95 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS:22001-23477 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in the GenBank (nucleotide sequences) database. Query and individual sequences were aligned using the TeraBLAST program available from TimeLogic, Crystal Bay, Nev. The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the RepeatMasker masking program for masking low complexity as described above.

Table 148 (inserted prior to claims) provides the alignment summaries having a p value of 1×10e-2 or less indicating substantial homology between the sequences of the present invention and those of the indicated public databases. Specifically, Table 148 provides: 1) the SEQ ID NO (“SEQ ID”) of the query sequence; 2) the sequence name (“SEQ NAME”) used as an internal identifier of the query sequence; 3) the accession number (“ACCESSION”) of the GenBank database entry of the homologous sequence; 4) a description of the GenBank sequences (“GENBANK DESCRIPTION”); and 5) the score of the similarity of the polynucleotide sequence and the GenBank sequence (“GENBANK SCORE”). The alignments provided in Table 148 are the best available alignment to a DNA sequence at a time just prior to filing of the present specification. Also incorporated by reference is all publicly available information regarding the sequence listed in Table 147 and their related sequences. The search program and database used for the alignment, as well as the calculation of the p value are also indicated. Full length sequences or fragments of the polynucleotide sequences can be used as probes and primers to identify and isolate the full length sequence of the corresponding polynucleotide.

TABLE 147 cDNA cDNA SEQ PROTEIN PROTEIN SEQ POLYNTD SEQ ID NAME SEQ ID NAME SEQ ID POLYNTD SEQ NAME 23386 DTT00087024.1 1478 DTP00087033.1 963 2467.H18.GZ43_360651 23386 DTT00087024.1 1478 DTP00087033.1 33 2505.B05.GZ43_366202 23387 DTT00089020.1 1479 DTP00089029.1 213 2367.l15.GZ43_346201 23388 DTT00171014.1 1480 DTP00171023.1 1006 2473.F14.GZ43_361367 23388 DTT00171014.1 1480 DTP00171023.1 1122 2489.A03.GZ43_362831 23389 DTT00514029.1 1481 DTP00514038.1 1113 2488.G02.GZ43_362590 23390 DTT00740010.1 1482 DTP00740019.1 952 2466.l08.GZ43_360281 23391 DTT00945030.1 1483 DTP00945039.1 945 2466.D19.GZ43_360172 23392 DTT01169022.1 1484 DTP01169031.1 482 2540.l17.GZ43_372216 23392 DTT01169022.1 1484 DTP01169031.1 914 2464.N05.GZ43_357997 23393 DTT01178009.1 1485 DTP01178018.1 113 2510.O21.GZ43_369382 23394 DTT01315010.1 1486 DTP01315019.1 1181 2496.F14.GZ43_364217 23395 DTT01503016.1 1487 DTP01503025.1 386 2538.M17.GZ43_371544 23396 DTT01555018.1 1488 DTP01555027.1 366 2538.C07.GZ43_371294 23396 DTT01555018.1 1488 DTP01555027.1 368 2538.D03.GZ43_371314 23396 DTT01555018.1 1488 DTP01555027.1 369 2538.D04.GZ43_371315 23397 DTT01685047.1 1489 DTP01685056.1 1177 2496.C08.GZ43_364139 23398 DTT01764019.1 1490 DTP01764028.1 267 2535.C23.GZ43_370158 23398 DTT01764019.1 1490 DTP01764028.1 771 2456.D04.GZ43_355904 23399 DTT01890015.1 1491 DTP01890024.1 1087 2482.J06.GZ43_359493 23399 DTT01890015.1 1491 DTP01890024.1 1042 2475.B20.GZ43_362045 23399 DTT01690015.1 1491 DTP01890024.1 1200 2497.L21.GZ43_364752 23400 DTT02243008.1 1492 DTP02243017.1 1224 2562.G21.GZ43_375628 23400 DTT02243008.1 1492 DTP02243017.1 1204 2497.P04.GZ43_364831 23400 DTT02243008.1 1492 DTP02243017.1 1025 2474.J19.GZ43_361852 23400 DTT02243008.1 1492 DTP02243017.1 1191 2497.D11.GZ43_364550 23401 DTT02367007.1 1493 DTP02367016.1 174 2366.P08.G243_345738 23402 DTT02671007.1 1494 DTP02671016.1 903 2464.H22.G243_357870 23402 DTT02671007.1 1494 DTP02671016.1 1055 2480.G11.G243 358658 23403 DTT02737017.1 1495 DTP02737026.1 385 2538.M16.GZ43_371543 23404 DTT02850005.1 1496 DTP02850014.1 992 2472.G03.GZ43_360996 23404 DTT02850005.1 1496 DTP02850014 1 1111 2488. F06.GZ43_362570 23404 DTT02850005.1 1496 DTP02850014.1 1039 2475.N08.GZ43_362321 23405 DTT02966016.1 1497 DTP02966025.1 103 2510.M14.GZ43_369327 23406 DTT03037029.1 1498 DTP03037038.1 9 2504.D16.G243_365877 23407 DTT03150008.1 1499 DTP03150017.1 428 2565.G20.GZ43_ 398256 23407 DTT03150008 1 1499 DTP03150017.1 585 2555.I12.GZ43_373363 23407 DTT03150008.1 1499 DTP03150017.1 235 2368.D08.GZ43_346458 23407 DTT031500081 1499 DTP03150017.1 1174 2491.P10.C243_363966 23408 DTT03367008.1 1500 DTP03367017.1 519 2506.E18.GZ43_366671 23408 DTT03367008.1 1500 DTP03367017.1 557 2542.P19.GZ43_373154 23409 DTT03630013.1 1501 DTP03630022.1 114 2510.O22.GZ43_369383 23410 DTT03881017 1 1502 DTP03881026.1 1251 2507.O12.GZ43_ 367289 23411 DTT039l3023.1 1503 DTP03913032.1 889 2459.P24.6243_357376 23412 DTT03978010.1 1504 DTP03978019.1 211 2367.G22.GZ43_346160 23413 DTT04070014.1 1505 DTP04070023.1 423 2565.D06.GZ43_398029 23413 DTT04070014.1 1505 DTP04070023.1 374 2538.F03GZ43_371362 23413 DTT04070014.1 1505 DTP04070023.1 17 2504.I13.GZ43_365994 23413 DTT04070014.1 1505 DTP04070023.1 692 2559.K12.GZ43_374947 23413 DTT04070014.1 1505 DTPO4070023.1 43 2505.E15.GZ43_366284 23413 DTT04070014.1 1505 DTP04070023.1 750 2561.M09.GZ43_376528 23413 DTT04070014.1 1505 DTP04070023.1 463 2540.H07.GZ43_372182 23413 DTT04070014.1 1505 DTP04070023.1 1069 2481.013.GZ43_358972 23414 DTT04084010.1 1506 DTP04084019.1 543 2542.D19.GZ43_372866 23415 DTT04160007.1 1507 0TP04160016.1 999 2472.M22.GZ43_361159 23416 DTT04302021.1 1508 DIPO4302030.1 1106 2483.O07.G243_359998 23417 DTT04378009.1 1509 DTP04378018.1 260 2368.O11.GZ43_346725 23418 DTT04403013.1 1510 DTP04403022.1 531 2506.M05.GZ43_366850 23419 DTT04414015.1 1511 DTP04414024.1 236 2368.D20.GZ43_346470 23420 DTT04660017.1 1512 DTP04660026.1 334 2537.D11.GZ43_370938 23420 DTT04660017.1 1512 DTP04660026.1 1244 2507.C03.GZ43_366992 23421 DTT04956054.1 1513 DTP04956063.1 379 2538.I17.GZ43_371448 23422 DTT04970018.1 1514 DTP04970027.1 363 2538.B03.GZ43_371266 23422 DTT04970018.1 1514 DTP04970027.1 259 2368.O03.GZ43_346717 23422 DTT04970018.1 1514 DTP04970027.1 1101 2483.K02.GZ43_359897 23422 DTT04970018.1 1514 DTP04970027.1 134 2365.F24.GZ43_345370 23423 DTT05205007.1 1515 DTP05205016.1 880 2459.J12.GZ43_357220 23424 DTT05571010.1 1516 DTP05571019.1 586 2555.J10.GZ43_373385 23425 DTT05650008.1 1517 DTP05650017.1 644 2557.L01.GZ43_374192 23426 DTT05742029.1 1518 DTP05742038.1 721 2560.K10.GZ43_375329 23426 DTT05742029.1 1518 DTP05742038.1 126 2365.D10.GZ43_345308 23426 DTT05742029.1 1518 DTP05742038.1 756 2561.I19.GZ43_376442 23427 DTT06137030.1 1519 DTP06137039.1 419 2565.B15.GZ43_398171 23428 DTT06161014.1 1520 DTP06161023.1 205 2367.F06.GZ43_346120 23429 DTT06706019.1 1521 DTP06706028.1 967 2467.D10.GZ43_360547 23430 DTT06837021.1 1522 DTP06837030.1 465 2540.I10.GZ43_372209 23431 DTT07040015.1 1523 DTP07040024.1 10 2504.E23.GZ43_365908 23432 DTT07088009.1 1524 DTP07088018.1 170 2366.J06.GZ43_345700 23432 DTT07088009.1 1524 DTP07088018.1 429 2565.H01.GZ43_397953 23433 DTT07182014.1 DTP07182023.1 306 2536.G22.GZ43_370637 23434 DTT07405044.1 1525 DTP07405053.1 703 2560.B11.GZ43_375114 23435 DTT07408020.1 1526 DTP07408029.1 956 2466.M02.GZ43_360371 23436 DTT07498014.1 1527 DTP07498023.1 529 2506.K20.GZ43_366817 23437 DTT07600010.1 1528 DTP07600019.1 902 2464.H17.GZ43_357865 23438 DTT08005024.1 1529 DTP08005033.1 1046 2475.N21.GZ43_362334 23439 DTT08098020.1 1530 DTP08098029.1 485 2540.M18.GZ43_372313 23440 DTT08167018.1 1531 DTP08167027.1 152 2365.N12.GZ43_345550 23440 DTT08167018.1 1531 DTP08167027.1 544 2542.F05.GZ43_372900 23441 DTT08249022.1 1532 DTP08249031.1 1235 2498.G15.GZ43_365010 23442 DTT08499022.1 1533 DTP08499031.1 452 2540.A24.GZ43_372031 23443 DTT08514022.1 1534 DTP08514031.1 508 2541.L12.GZ43_372667 23444 DTT08527013.1 1535 DTP08527022.1 109 2510.N14.GZ43_369351 23444 DTT08527013.1 1535 DTP08527022.1 394 2554.A16.GZ43_375863 23444 DTT08527013.1 1535 DTP08527022.1 1128 2489.F09.GZ43_362957 23444 DTT08527013.1 1535 DTP08527022.1 569 2555.F16.GZ43_373295 23445 DTT08595020.1 1536 DTP08595029.1 413 2554.N09.GZ43_376168 23446 DTT08711019.1 1537 DTP08711028.1 472 2540.C19.GZ43_372074 23447 DTT08773020.1 1538 DTP08773029.1 687 2559.I12.GZ43_374899 23448 DTT08874012.1 1539 DTP08874021.1 356 2537.P14.GZ43_371229 23449 DTT09387018.1 1540 DTP09387027.1 762 2561.P19.GZ43_376610 23450 DTT09396022.1 1541 DTP09396031.1 1140 2489.M11.GZ43_363127 23451 DTT09553027.1 1542 DTP09553036.1 54 2505.J22.GZ43_366411 23452 DTT09604016.1 1543 DTP09604025.1 1100 2483.J07.GZ43_359878 23453 DTT09705033.1 1544 DTP09705042.1 323 2536.O22.GZ43_370829 23454 DTT09742009.1 1545 DTP09742018.1 766 2456.B12.GZ43_355864 23454 DTT09742009.1 1545 DTP09742018.1 563 2542.N21.GZ43_373108 23455 DTT09753017.1 1546 DTP09753026.1 910 2464.L02.GZ43_357946 23456 DTT09793019.1 1547 DTP09793028.1 904 2464.I04.GZ43_357876 23457 DTT09796028.1 1548 DTP09796037.1 189 2366.L21.GZ43_345942 23458 DTT10221016.1 1549 DTP10221025.1 592 2556.C19.GZ43_373610 23459 DTT10360040.1 1550 DTP10360049.1 1045 2475.M20.GZ43_362309 23460 DTT10539016.1 1551 DTP10539025.1 527 2506.J20.GZ43_366793 23461 DTT10564022.1 1552 DTP10564031.1 1035 2475.H06.GZ43_362175 23462 DTT10683041.1 1553 DTP10683050.1 561 2542.K21.GZ43_373036 23463 DTT10819011.1 1554 DTP10819020.1 796 2457.C19.GZ43_356279 23463 DTT10819011.1 1554 DTP10819020.1 143 2365.J14.GZ43_345456 23463 DTT10819011.1 1554 DTP10819020.1 1023 2474.I06.GZ43_361815 23464 DTT11363027.1 1555 DTP11363036.1 540 2542.C20.GZ43_372843 23465 DTT11479018.1 1556 DTP11479027.1 521 2506.G24.GZ43_366725 23466 DTT11483012.1 1557 DTP11483021.1 877 2459.H09.GZ43_357169 23467 DTT11548015.1 1558 DTP11548024.1 422 2565.C17.GZ43_398204 23468 DTT11730017.1 1559 DTP11730026.1 264 2535.B09.GZ43_370120 23469 DTT11791010.1 1560 DTP11791019.1 518 2506.E12.GZ43_366665 23470 DTT11864036.1 1561 DTP11864045.1 778 2456.H07.GZ43_356003 23471 DTT11902028.1 1562 DTP11902037.1 1144 2490.B06.GZ43_363242 23472 DTT11915017.1 1563 DTP11915026.1 591 2556.C11.GZ43_373602 23472 DTT11915017.1 1563 DTP11915026.1 1021 2474.G17.GZ43_361778 23472 DTT11915017.1 1563 DTP11915026.1 1163 2491.C13.GZ43_363657 23473 DTT11966040.1 1564 DTP11966049.1 1216 2562.E14.GZ43_375573 23473 DTT11966040.1 1564 DTP11966049.1 818 2457.L21.GZ43_356497 23473 DTT11966040.1 1564 DTP11966049.1 532 2506.M13.GZ43_366858 23474 DTT12042027.1 1565 DTP12042036.1 874 2459.G01.GZ43_357137 23475 DTT12201062.1 1566 DTP12201071.1 759 2561.O17.GZ43_376584 23475 DTT12201062.1 1566 DTP12201071.1 1207 2562.B09.GZ43_375496 23476 DTT12470020.1 1567 DTP12470029.1 1124 2489.A13.GZ43_362841 23476 DTT12470020.1 1567 DTP12470029.1 799 2457.D12.GZ43_356296 23476 DTT12470020.1 1567 DTP12470029.1 690 2559.J02.GZ43_374913 23476 DTT12470020.1 1567 DTP12470029.1 568 2555.E20.GZ43_373275 23477 DTT12550009.1 1568 DTP12550018.1 12 2504.G01.GZ43_365934

TABLE 148 GENBANK SEQ ID SEQ NAME ACCESSION GENBANK DESCRIPTION SCORE 22006 2504.C08.GZ43_(—) AP000321 gi|4835690|dbj|AP000321.1AP000321 1.6E−31 365845 Homo sapiens genomic DNA, chromosome 21q22.1, D21S226-AML region, clone: Q82F5, complete sequence 22007 2504.C11.GZ43_(—) AP002938 gi|16267134|dbj|AP002938.1AP002938 4.8E−58 365848 Hoplostethus japonicus mitochondrial DNA, complete genome 22009 2504.D16.GZ43_(—) AK023496 gi|10435445|dbj|AK023496.1AK023496 0 365877 Homo sapiens cDNA FLJ13434 fis, clone PLACE1002578 22010 2504.E23.GZ43_(—) M80340 gi|339767|gb|M80340.1HUMTNL12 6.1E−182 365908 Human transposon L1.1 with a base deletion relative to L1.2B resulting in a premature stop codon in t 22011 2504.F20.GZ43_(—) AE007289 gi|14524175|gb|AE007289.1AE007289 2.1E−98 365929 Sinorhizobium meliloti plasmid pSymA section 95 of 121 of the complete plasmid sequence 22017 2504.I13.GZ43_(—) AJ312523 gi|12830519|emb|AJ312523.1GGO312523 1.1E−44 365994 Gorilla gorilla gorilla Xq13.3 chromosome non-coding sequence, isolate G167W 22031 2504.O12.GZ43_(—) AF342020 gi|12961941|gb|AF342020.1AF342020 1.1E−90 366137 Sclerotinia sclerotiorum strain LES-1 28S ribosomal RNA gene, partial sequence; intergenic spacer 22033 2505.B05.GZ43_(—) U93571 gi|2072968|gb|U93571.1HSU93571 1.1E−226 366202 Human L1 element L1.24 p40 gene, complete cds 22037 2505.C17.GZ43_(—) AJ325713 gi|158701107|emb|AJ325713.1HSA325713 1.4E−21 366238 Homo sapiens genomic sequence surrounding NotI site, clone NB1-110S 22040 2505.D03.GZ43_(—) AJ224335 gi|3413799|emb|AJ224335.1HSAJ4335 5.2E−71 366248 Homo sapien mRNA for putative secretory protein, hBET3 22043 2505.E15.GZ43_(—) AB030001 gi|7416074|dbj|AB030001.1AB030001 8.1E−55 366284 Homo sapiens gene for SGRF, complete cds 22046 2505.G16.GZ43_(—) AE005683 gi|13421186|gb|AE005683.1AE005683 3.6E−63 366333 Caulobacter crescentus section 9 of 359 of the complete genome 22048 2505.I04.GZ43_(—) AF255613 gi|8925326|gb|AF255613.1AF255613 7.9E−73 366369 Homo sapiens teratoma-associated tyrosine kinase (TAPK) gene, exons 1 through 6 and partial cds 22063 2505.O09.GZ43_(—) AF053644 gi|3598786|gb|AF053644.1HSCSE1G2 9.4E−45 366518 Homo sapiens cellular apoptosis susceptibility protein (CSE1) gene, exon 2 22072 2510.C10.GZ43_(—) AB002353 gi|2224650|dbj|AB002353.1AB002353 1.4E−71 369083 Human mRNA for KIAA0355 gene, complete cds 22078 2510.G06.GZ43_(—) AF084935 gi|3603422|gb|AF084935.1AF084935 8.9E−24 369175 Homo sapiens galactokinase (GALK1) gene, partial cds 22089 2510.J11.GZ43_(—) AK024617 gi|10436933|dbj|AK024617.1AK024617 0 369252 Homo sapiens cDNA: FLJ20964 fis, clone ADSH00902 22102 2510.L21.GZ43_(—) AK023677 gi|10435673|dbj|AK023677.1AK023677 1.2E−90 369310 Homo sapiens cDNA FLJ13615 fis, clone PLACE1010896, weakly similar to NUF1 PROTEIN 22109 2510.N14.GZ43_(—) AF271388 gi|8515842|gb|AF271388.1AF271388 0 369351 Homo sapiens CMP-N-acetylneuraminic acid synthase mRNA, complete cds 22115 2510.O23.GZ43_(—) AF113169 gi|4164598|gb|AF113169.1AF113169 2.2E−39 369384 Homo sapiens glandular kallikrein enhancer region, complete sequence 22124 2365.C20.GZ43_(—) AF069489 gi|3560568|gb|AF069489.1HSPDE4A3 6.6E−24 345294 Homo sapiens cAMP specific phosphodiesterase 4A varient pde46 (PDE4A) gene, exons 2 through 13 and 22134 2365.F24.GZ43_(—) AK012908 gi|12849956|dbj|AK012908.1AK012908 2.9E−224 345370 Mus musculus 10, 11 days embryo cDNA, RIKEN full-length enriched library, clone: 2810046L04, full 22143 2365.J14.GZ43_(—) BC007999 gi|14124949|gb|BC007999.1BC007999 4.4E−56 345456 Homo sapiens, hypothetical protein FLJ10759, clone MGC: 15757 IMAGE: 3357436, mRNA, complete cds 22152 2365.N12.GZ43_(—) U20391 gi|1483626|gb|U20391.1HSU20391 3.9E−41 345550 Human folate reeceptor (FOLR1) gene, complete cds 22162 2366.E03.GZ43_(—) AB025285 gi|5917586|dbj|AB025285.1AB025285 4.3E−30 345647 Homo sapiens c-ERBB-2 gene, exons 1′, 2′, 3′, 4′ 22163 2366.J03.GZ43_(—) M15885 gi|338414|gb|M15885.1HUMSPP Human 1.1E−68 345652 prostate secreted seminal plasma protein mRNA, complete cds 22170 2366.J06.GZ43_(—) AF326517 gi|15080738|gb|AF326517.1AF326517 0 345700 Abies grandis pinene synthase gene, partial cds 22182 2366.K13.GZ43_(—) U27333 gi|967202|gb|U27333.1HSU27333 Human 2.5E−44 345813 alpha(1,3) fucosyltransferase (FUT6) mRNA, major transcript I, complete cds 22189 2366.L21.GZ43_(—) AF272390 gi|8705239|gb|AF272390.1AF272390 1.4E−290 345942 Homo sapiens mysoin 5c (MYO5C) mRNA, complete cds 22195 2367.B10.GZ43_(—) AJ279823 gi|11932035|emb|AJ279823.1ASF279823 1.4E−231 346028 Ascovirus SfA V1b partial pol gene for DNA polymerase, Pol2-Pol3-Pol1 fragment 22198 2367.C12.GZ43_(—) BC014669 gi|15779227|gb|BC014669.1BC014669 2.9E−57 346054 Homo sapiens, clone IMAGE: 4849317, mRNA, partial cds 22200 2367.D18.GZ43_(—) AE008517 gi|15459138|gb|AE008517.1AE008517 1.4E−34 346084 Streptococcus pneumoniae R6 section 133 of 184 of the complete genome 22205 2367.F06.GZ43_(—) AJ330464 gi|15874882|emb|AJ330464.1HSA330464 3.1E−100 346120 Homo sapiens genomic sequence surrounding NotI site, clone NR1-IL7C 22206 2367.F13.GZ43_3 AY035075 gi|14334803|gb|AY035075.1 Arabidopsis 4.1E−229 346127 thaliana putative H+-transporting ATPase (AT4g30190) mRNA, complete cds 22208 2367.G13.GZ43_(—) AK025355 gi|10437854|dbj|AK025355.1AK025355 1.8E−58 346151 Homo sapiens cDNA: FLJ21702 fis, clone COL09874 22209 2367.G17.GZ43_(—) AK000293 gi|7020278|dbj|AK000293.1AK000293 4.4E−34 346155 Homo sapiens cDNA FLJ20286 fis, clone HEP04358 22210 2367.G20.GZ43_(—) AL137592 gi|6808332|emb|AL137592.1HSM802347 1.6E−60 346158 Homo sapiens mRNA; cDNA DKFZp434L0610 (from clone DKFZp434L0610); partial cds 22211 2367.G22.GZ43_(—) BC015529 gi|15930193|gb|BC015529.1BC015529 9.7E−60 346160 Homo sapiens, Similar to ribose 5- phosphate isomerase A, clone MGC: 9441 IMAGE: 3904718, mRNA, comp 22213 2367.I15.GZ43_(—) AF324172 gi|12958747|gb|AF324172.1AF324172 4.8E−65 346201 Dictyophora indusiata strain ASI 32001 internal transcribed spacer 1, partial sequence; 5.8S ribo 22217 2367.K24.GZ43_(—) AF009251 gi|2352833|gb|AF009251.1CLCN6HUM05 3.8E−62 346258 Homo sapiens putative chloride channel gene (CLCN6), exon 6 22219 2367.M06.GZ43_(—) AF178322 gi|13344845|gb|AF178322.1AF178322 1.5E−43 346288 Schmidtea mediterranea cytochrome oxidase C subunit I (COI) gene, partial cds; mitochondrial gene 22220 2367.M14.GZ43_(—) AK026286 gi|10439097|dbj|AK026286.1AK026286   1E−300 346296 Homo sapiens cDNA: FLJ22633 fis, clone HSI06502 22221 2367.M16.GZ43_(—) AF368920 gi|14039926|gb|AF368920.1AF368920 1.6E−83 346298 Caenorhabditis elegans voltage-dependent calcium channel alpha13 subunit (cca-1) mRNA, complete c 22224 2367.N16.GZ43_(—) Z78727 gi|1508005|emb|Z78727.1HSPA15B9 1.3E−37 346322 H. sapiens flow-sorted chromosome 6 HindIII fragment, SC6pA15B9 22231 2368.B18.GZ43_(—) AK000293 gi|7020278|dbj|AK000293.1AK000293   5E−34 346420 Homo sapiens cDNA FLJ20286 fis, clone HEP04358 22235 2368.D08.GZ43_(—) AJ276936 gi|12214232|emb|AJ276936.1NME276936 0 346458 Neisseria meningitidis partial tbpB gene for transferrin binding protein B subunit, allele 66, 22245 2368.I04.GZ43_(—) AY042191 gi|15546022|gb|AY042191.1 Mus 3.1E−26 346574 musculus RF-amide G protein-coupled receptor (MrgA1) mRNA, complete cds 22249 2368.K21.GZ43_(—) AJ310931 gi|15718363|emb|AJ310931.1HSA310931   7E−55 346639 Homo sapiens mRNA for myosin heavy chain 22252 2368.M19.GZ43_(—) AK025595 gi|10438161|dbj|AK025595.1AK025595 4.7E−21 346685 Homo sapiens cDNA: FLJ21942 fis, clone HEP04527 22257 2368.N15.GZ43_(—) AK014328 gi|12852104|dbj|AK014328.1AK014328 3.1E−103 346705 Mus musculus 14, 17 days embryo head cDNA, RIKEN full-length enriched library, clone: 3230401M21, 22258 2368.N23.GZ43_(—) AL391428 gi|9864373|emb|AL391428.1AL391428 4.8E−28 346713 Human DNA sequence from clone RP11- 60P19 on chromosome 1, complete sequence [Homo sapiens] 22259 2368.O03.GZ43_(—) AK012908 gi|12849956|dbj|AK012908.1AK012908 2.1E−227 346717 Mus musculus 10, 11 days embryo cDNA, RIKEN full-length enriched library, clone: 2810046L04, full 22260 2368.O11.GZ43_(—) AF102129 gi|5922722|gb|AF102129.1AF102129 2.5E−103 346725 Rattus norvegicus KPL2 (Kp12) mRNA, complete cds 22264 2535.B09.GZ43_(—) AF292648 gi|12656358|gb|AF292648.1AF292648   2E−39 370120 Mus musculus zinc finger 202 ml (Znf202) mRNA, complete cds 22267 2535.C23.GZ43_(—) AF307053 gi|12018057|gb|AF307053.1AF307053 0 370158 Thermococcus litoralis sugar kinase, trehalose/maltose binding protein (malE), trehalose/maltose 22269 2535.F05.GZ43_(—) AF367433 gi|14486704|gb|AF367433.1AF367433 3.8E−38 370212 Lotus japonicus phosphatidylinositol transfer-like protein III (LjPLP-III) mRNA, complete cds 22276 2535.L03.GZ43_(—) AK000099 gi|7019966|dbj|AK000099.1AK000099 7.1E−52 370354 Homo sapiens cDNA FLJ20092 fis, clone COL04215 22280 2535.O07.GZ43_(—) BC008425 gi|14250051|gb|BC008425.1BC008425 3.8E−34 370430 Homo sapiens, clone MGC: 14582 IMAGE: 4246114, mRNA, complete cds 22282 2535.P02.GZ43_(—) NM_024074 gi|13129059|ref|NM_024074.1 Homo 2.4E−23 370449 sapiens hypothetical protein MGC3169 (MGC3169), mRNA 22292 2536.A22.GZ43_(—) AF310311 gi|13517433|gb|AF310311.1AF310311 0 370493 Homo sapiens isolate Nigeria 9 membrane protein CH1 gene, partial cds 22297 2536.D17.GZ43_(—) AF015148 gi|2353128|gb|AF015148.1AF015148 1.6E−46 370560 Homo sapiens clone HS19.2 Alu-Ya5 sequence 22303 2536.G05.GZ43_(—) AF045605 gi|3228525|gb|AF045605.1AF045605 6.2E−77 370620 Homo sapiens germline chromosome 11, 11q13 region 22305 2536.G21.GZ43_(—) AK026490 gi|10439363|dbj|AK026490.1AK026490 3.5E−143 370636 Homo sapiens cDNA: FLJ22837 fis, clone KAIA4417 22306 2536.G22.GZ43_(—) NC_002707 gi|13540758|ref|NC_002707.1 Anguilla 2.3E−39 370637 japonica mitochondrion, complete genome 22309 2536.I05.GZ43_(—) AK000099 gi|7019966|dbj|AK000099.1AK000099 3.4E−63 370668 Homo sapiens cDNA FLJ20092 fis, clone COL04215 22310 2536.I15.GZ43_(—) AB013897 gi|6177784|dbj|AB013897.1AB013897 5.1E−53 370678 Homo sapiens mRNA for HKR1, partial cds 22313 2536.J11.GZ43_(—) AK023448 gi|10435386|dbj|AK023448.1AK023448 0 370698 Homo sapiens cDNA FLJ13386 fis, clone PLACE1001104, weakly similar to MYOSIN HEAVY CHAIN, NON-MU 22314 2536.K12.GZ43_(—) U14573 gi|551542|gb|U14573.1HSU14573   1E−96 370723 ***ALU WARNING: Human Alu-Sq subfamily consensus sequence 22319 2536.N05.GZ43_(—) AK001347 gi|7022548|dbj|AK001347.1AK001347 6.7E−43 370788 Homo sapiens cDNA FLJ10485 fis, clone NT2RP2000195 22320 2536.N20.GZ43_(—) Y15724 gi|3021395|emb|Y15724.1HSSERCA1 1.9E−27 370803 Homo sapiens SERCA3 gene, exons 1–7 (and joined CDS) 22330 2537.B07.GZ43_(—) X69516 gi|288876|emb|X69516.1HSFOLA 2.8E−60 370886 H. sapiens gene for folate receptor 22334 2537.D11.GZ43_(—) NM_025080 gi|13376633|ref|NM_025080.1 Homo 8.7E−289 370938 sapiens hypothetical protein FLJ22316 (FLJ22316), mRNA 22338 2537.G05.GZ43_(—) L04193 gi|187144|gb|L04193.1HUMLIMGP 7.4E−52 371004 Human lens membrane protein (mp19) gene, exon 11 22341 2537.I03.GZ43_(—) Z78727 gi|1508005|emb|Z78727.1HSPA15B9 1.7E−37 371050 H. sapiens flow-sorted chromosome 6 HindIII fragment, SC6pA15B9 22345 2537.K17.GZ43_(—) AL603947 gi|15384818|emb|AL603947.1UMA0006 9.3E−76 371112 Ustilago maydis gene for predicted plasmamembrane-ATPase 22350 2537.N23.GZ43_(—) AF242865 gi|985870|gb|AF242865.1AF242862S4 2.4E−30 371190 Homo sapiens coxsackie virus and adenovirus receptor (CXADR) gene, exon 7 and complete cds 22352 2537.O05.GZ43_(—) AB060827 gi|13874462|dbj|AB060827.1AB060827 2.2E−24 371196 Macaca fascicularis brain cDNA clone: QtrA-10256, full insert sequence 22356 2537.P14.GZ43_(—) AK026442 gi|10439307|dbj|AK026442.1AK026442 6.3E−256 371229 Homo sapiens cDNA: FLJ22789 fis, clone KAIA2171 22361 2538.A10.GZ43_(—) AK001432 gi|7022685|dbj|AK001432.1AK001432 1.9E−52 371249 Homo sapiens cDNA FLJ10570 fis, clone NT2RP2003117 22363 2538.B03.GZ43_(—) AK013900 gi|1285449|dbj|AK013900.1AK013900 1.2E−201 371266 Mus musculus 12 days embryo head cDNA, RIKEN full-length enriched library, clone: 3010026L22, ful 22366 2538.C07.GZ43_(—) AK022973 gi|10434673|dbj|AK022973.1AK022973 0 371294 Homo sapiens cDNA FLJ12911 fis, clone NT2RP2004425, highly similar to Mus musculus axotrophin mR 22367 2538.C14.GZ43_(—) M87914 gi|174891|gb|M87914.1HUMALNE461   2E−89 371301 Human carcinoma cell-derived Alu RNA transcript, clone NE461 22368 2538.D03.GZ43_(—) AK022973 gi|10434673|dbj|AK022973.1AK022973 4.3E−275 371314 Homo sapiens cDNA FLJ12911 fis, clone NT2RP2004425, highly similar to Mus musculus axotrophin mR 22369 2538.D04.GZ43_(—) AK022973 gi|10434673|dbj|AK022973.1AK022973 1.3E−287 371315 Homo sapiens cDNA FLJ12911 fis, clone NT2RP2004425, highly similar to Mus musculus axotrophin mR 22371 2538.E01.GZ43_(—) AF074397 gi|3916231|gb|AF074397.1AF074397   4E−40 371336 Homo sapiens anti-mullerian hormone type II receptor (AMHR2) gene, promoter region and partial cds 22374 2538.F03.GZ43_(—) L34639 gi|598203|gb|L34639.1HUMPECAM09 1.5E−43 371362 Homo sapiens platelet/endothelial cell adhesion molecule-1 (PECAM-1) gene, exon 6 22375 2538.H02.GZ43_(—) AF220173 gi|9651700|gb|AF220173.1AF220172S2 2.5E−39 371409 Homo sapiens acid ceramidase (ASAH) gene, exons 2 through 4 22379 2538.I17.GZ43_(—) AF050179 gi|3319283|gb|AE050179.1AF050179 4.9E−41 371448 Homo sapiens CENP-C binding protein (DAXX) mRNA, complete cds 22380 2538.J10.GZ43_(—) AY035075 gi|14334803|gb|AY035075.1 Arabidopsis 3.5E−245 371465 thaliana putative H+-transporting ATPase (AT4g30190) mRNA, complete cds 22381 2538.K17.GZ43_(—) AK022749 gi|10434332|dbj|AK022749.1AK022749 1.5E−31 371496 Homo sapiens cDNA FLJ12687 fis, clone NT2RM4002532, weakly similar to PROTEIN HOM1 22385 2538.M16.GZ4_(—) AF375410 gi|14030638|gb|AF375410.1AF375410 1.9E−53 371543 Arabidopsis thaliana At2g43970/F6E13.10 gene, complete cds 22386 2538.M17.GZ43_(—) AK025473 gi|10437996|dbj|AK025473.1AK025473 3.2E−282 371544 Homo sapiens cDNA: FLJ21820 fis, clone HEP01232 22389 2538.P16.GZ43_(—) AK026286 gi|10439097|dbj|AK026286.1AK026286 0 371615 Homo sapiens cDNA: FLJ22633 fis, clone HSI06502 22391 2554.A06.GZ43_(—) AK001324 gi|7022509|dbj|AK001324.1AK001324   4E−44 375853 Homo sapiens cDNA FLJ10462 fis, clone NT2RP1001494, weakly similar to MALE STERILITY PROTEIN 2 22394 2554.A16.GZ43_(—) AF271388 gi|8515842|gb|AF271388.1AF271388 0 375863 Homo sapiens CMP-N-acetylneuraminic acid synthase mRNA, complete cds 22406 2554.I15.GZ43 AY050376 gi|15215695|gb|AY050376.1 Arabidopsis 8.8E−27 376054 thaliana AT3g16950/K14A17_7 mRNA, complete cds 22415 2554.P16.GZ43_(—) AK022368 gi|10433751|dbj|AK022368.1AK022368 6.7E−46 376223 Homo sapiens cDNA FLJ12306 fis, clone MAMMA 1001907 22418 2565.B13.GZ43_(—) AL050012 gi|4884261|emb|AL050012.1HSM800354   1E−44 398139 Homo sapiens mRNA; cDNA DKFZp564K133 (from clone DKFZp564K133) 22419 2565.B15.GZ43_(—) AY049285 gi|15146287|gb|AY049285.1 Arabidopsis 2.1E−62 398171 thaliana AT3g58570/F14P22_160 mRNA, complete cds 22422 2565.C17.GZ43_(—) M24543 gi|341200|gb|M24543.1 HUMPSANTIG 2.5E−49 398204 Human prostate-specific antigen (PA) gene, complete cds 22423 2565.D06.GZ43_(—) AF331321 gi|13095271|gb|AF331321.1AF331321 4.7E−30 398029 HIV1 isolate T7C44 from the Netherlands nonfunctional pol polyprotein gene, partial sequence 22428 2565.G20.GZ43_(—) AJ276936 gi|1221232|emb|AJ276936.1NME276936 0 398256 Neisseria meningitidis partial tbpB gene for transferrin binding protein B subunit, allele 66, 22429 2565.H01.GZ43_(—) AF326517 gi|15080738|gb|AF326517.1AF326517   1E−300 397953 Abies grandis pinene synthase gene, partial cds 22433 2565.I22.GZ43_(—) AK001926 gi|7023492|dbj|AK001926.1AK001926 8.9E−295 398290 Homo sapiens cDNA FLJ11064 fis, clone PLACE1004824 22442 2565.M14.GZ43_(—) AF275699 gi|12275949|gb|AF275699.1AF275699 1.4E−21 398166 Unidentified Hailaer soda lake bacterium F16 16S ribosomal RNA gene, partial sequence 22447 2565.O07.GZ43_(—) AK024752 gi|10437118|dbj|AK024752.1AK024752 4.3E−51 398056 Homo sapiens cDNA: FLJ21099 fis, clone CAS04610 22452 2540.A24.GZ43_(—) Z69920 gi|1217632|emb|Z69920.1HS91K3D 1.1E−41 372031 Human DNA sequence from cosmid 91K3, Huntington's Disease Region, chromosome 4p16.3 22463 2540.H07.GZ43_(—) AE008025 gi|15155943|gb|AE008025.1AE008025 1.7E−40 372182 Agrobacterium tumefaciens strain C58 circular chromosome, section 83 of 254 of the complete seque 22465 2540.I10.GZ43_(—) AK000658 gi|7020892|dbj|AK000658.1AK000658 1.3E−53 372209 Homo sapiens cDNA FLJ20651 fis, clone KAT01814 22468 2540.M22.GZ43_(—) AF375597 gi|14150816|gb|AF375597.1AF375596S2 0 372317 Mus musculus medium and short chain L-3- hydroxyacyl-Coenzyme A dehydrogenase (Mschad) gene, exo 22472 2540.C19.GZ43_(—) AB019559 gi|4579750|dbj|AB019559.1AB019559 3.1E−24 372074 Sus scrofa mRNA for 130 kDa regulatory subunit of myosin phosphatase, partial cds 22477 2540.F15.GZ43_(—) AY016428 gi|13891961|gb|AY016428.1 Plasmodium 2.2E−33 372142 falciparum isolate Fas 30-6-7 apical membrane antigen-1 (AMA-1) gene, partial cds 22485 2540.M18.GZ43_(—) AJ331177 gi|15875595|emb|AJ331177.1HSA331177 7.7E−237 372313 Homo sapiens genomic sequence surrounding NotI site, clone NL1-ZF18RS 22507 2541.L08.GZ43_(—) BC003673 gi|13277537|gb|BC003673.1BC003673 2.6E−53 372663 Homo sapiens, protamine 1, clone MGC: 12307 IMAGE: 3935638, mRNA, complete cds 22508 2541.L12.GZ43_(—) AJ297708 gi|12055486|emb|AJ297708.1RNO297708 9.4E−45 372667 Rattus norvegicus RT6 gene for T cell differentiation marker RT6.2, exons 1–8 22514 2506.C15.GZ43_(—) AE007488 gi|14973493|gb|AE007488.1AE007488 1.4E−287 366620 Streptococcus pneumoniae TIGR4 section 171 of 194 of the complete genome 22519 2506.E18.GZ4_(—) AK025164 gi|10437625|dbj|AK025164.1AK025164 0 366671 Homo sapiens cDNA: FLJ21511 fis, clone COL05748 22521 2506.G24.GZ43_(—) AY030962 gi|13736961|gb|AY030962.1 HIV-1 isolate, 9.1E−233 366725 NC3964-1999 from USA pol polyprotein (pol) gene, partial cds 22527 2506.J20.GZ43_(—) AF152924 gi|5453323|gb|AF152924.1AF152924 Mus 2.3E−79 366793 musculus syntaxin4-interacting protein synip mRNA, complete cds 22528 2506.J22.GZ43_(—) AK000169 gi|7020080|dbj|AK000169.1AK000169 1.8E−99 366795 Homo sapiens cDNA FLJ20162 fis, clone COL09280 22531 2506.M05.GZ43_(—) AE007580 gi|15023517|gb|AE007580.1AE007580 2.1E−217 366850 Clostridium acetobutylicum ATCC824 section 68 of 356 of the complete genome 22534 2506.P07.GZ43_(—) AF035442 gi|3142369|gb|AF035442.1AF035442   1E−44 366924 Homo sapiens VAV-like protein mRNA, partial cds 22540 2542.C20.GZ43_(—) AE007424 gi|14972724|gb|AE007424.1AE007424 2.3E−42 372843 Streptococcus pneumoniae TIGR4 section 107 of 194 of the complete genome 22543 2542.D19.GZ43_(—) BC008333 gi|14249906|gb|BC008333.1BC008333 5.3E−284 372866 Homo sapiens, clone IMAGE: 3506145, mRNA, partial cds 22544 2542.F05.GZ43_(—) AK024179 gi|10436495|dbj|AK024179.1AK024179 2.4E−41 372900 Homo sapiens cDNA FLJ14117 fis, clone MAMMA1001785 22553 2542.M09.GZ43_(—) AK022973 gi|1043673|dbj|AK022973.1AK022973 5.8E−243 373072 Homo sapiens cDNA FLJ12911 fis, clone NT2RP2004425, highly similar to Mus musculus axotrophin mR 22557 2542.P19.GZ43_(—) AK025164 gi|10437625|dbj|AK025164.1AK025164 0 373154 Homo sapiens cDNA: FLJ21511 fis, clone COL05748 22562 2542.M24.GZ43_(—) AK022173 gi|10433509|dbj|AK022173.1AK022173 1.2E−284 373087 Homo sapiens cDNA FLJ12111 fis, clone MAMMA1000025 22563 2542.N21.GZ43_(—) AF025409 gi|2582414|gb|AF025409.1AF025409   2E−70 373108 Homo sapiens zinc transporter 4 (ZNT4) mRNA, complete cds 22567 2555.D22.GZ43_(—) AL1576971 gi|11121002|emb|AL157697.11AL157697 1.1E−87 373253 Human DNA sequence from clone RP5- 1092C14 on chromosome 6, complete sequence [Homo sapiens] 22568 2555.E20.GZ43_(—) AK026618 gi|10439509|dbj|AK026618.1AK026618 0 373275 Homo sapiens cDNA: FLJ22965 fis, clone KAT10418 22569 2555.F16.GZ43_(—) AF271388 gi|8515842|gb|AF271388.1AF271388 0 373295 Homo sapiens CMP-N-acetylneuraminic acid synthase mRNA, complete cds 22574 2555.K17.GZ43_(—) AK026686 gi|10439593|dbj|AK026686.1AK026686 1.8E−23 373416 Homo sapiens cDNA: FLJ23033 fis, clone LNG02005 22578 2555.P22.GZ43_(—) AF087913 gi|5081331|gb|AF087913.1AF087913 5.8E−74 373541 Human endogenous retrovirus HERV-P- T47D 22579 2555.A11.GZ43_(—) NC_000957 gi|11497445|ref|NC_000957.1 Borrelia 1.3E−57 373170 burgdorferi plasmid 1p5, complete sequence 22585 2555.I12.GZ43_(—) AJ276936 gi|12214232|emb|AJ276936.1NME276936 1.6E−237 373363 Neisseria meningitidis partial tbpB gene for transferrin binding protein B subunit, allele 66, 22589 2556.A02.GZ43_(—) AE007289 gi|14524175|gb|AE007289.1AE007289   2E−55 373545 Sinorhizobium meliloti plasmid pSymA section 95 of 121 of the complete plasmid sequence 22591 2556.C11.GZ43_(—) AY039252 gi|15418981|gb|AY039252.1 Macaca 3.1E−29 373602 mulatta immunoglobulin alpha heavy chain constant region (IgA) gene, IgA-C.II allele, partial cds 22602 2556.H15.GZ43_(—) AK021966 gi|10433275|dbj|AK021966.1AK021966 1.6E−70 373726 Homo sapiens cDNA FLJ11904 fis, clone HEMBB1000048 22620 2557.B22.GZ43_(—) AB071392 gi|15721873|dbj|AB071392.1AB071392 1.2E−25 373973 Expression vector pAQ-EX1 DNA, complete sequence 22627 2557.J14.GZ43_(—) AK023721 gi|10435737|dbj|AK023721.1AK023721 1.6E−209 374157 Homo sapiens cDNA FLJ13659 fis, clone PLACE1011576, moderately similar to Human Kruppel related 22635 2557.N14.GZ43_(—) AB013897 gi|6177784|dbj|AB013897.1AB013897   1E−44 374253 Homo sapiens mRNA for HKR1, partial cds 22648 2558.B24.GZ43_(—) AB064318 gi|14595115|dbj|AB064318.1AB064318 4.6E−28 374359 Comamonas testosteroni gene for 16S rRNA, partial sequence 22657 2558.G07.GZ43_(—) M92069 gi|337698|gb|M92069.1HUMRTVLC 6.7E−46 374462 Human retrovirus-like sequence-isoleucine c (RTVL-Ic) gene, Alu repeats 22661 2558.H17.GZ43_(—) AK023812 gi|10435860|dbj|AK023812.1AK023812 5.2E−31 374496 Homo sapiens cDNA FLJ13750 fis, clone PLACE3000331 22662 2558.J01.GZ43_(—) AK023448 gi|10435386|dbj|AK023448.1AK023448 4.8E−278 374528 Homo sapiens cDNA FLJ13386 fis, clone PLACE1001104, weakly similar to MYOSIN HEAVY CHAIN, NON-MU 22666 2558.K02.GZ43_(—) U14573 gi|551542|gb|U14573.1HSU14573 1.3E−62 374553 ***ALU WARNING: Human Alu-Sq subfamily consensus sequence 22683 2559.D05.GZ43_(—) AF338713 gi|14039582|gb|AF338713.1AF338713   4E−297 374772 Casuarius casuarius mitochondrion, partial genome 22687 2559.I12.GZ43_(—) AY036096 gi|14486435|gb|AY036096.1 HIV-1 isolate 1.4E−41 374899 L2Q2P from Belgium reverse transcriptase (pol) gene, partial cds 22690 2559.J02.GZ43_(—) AK026618 gi|10439509|dbj|AK026618.1AK026618 0 374913 Homo sapiens cDNA: FLJ22965 fis, clone KAT10418 22692 2559.K12.GZ43_(—) Z96776 gi|2181853|emb|Z96776.1HS9QT023 5.1E−52 374947 H. sapiens telomeric DNA sequence, clone 9QTEL023, read 9QTELOO023.seq 22694 2559.L09.GZ43_(—) AE007426 gi|14972746|gb|AE007426.1AE007426 8.1E−21 374968 Streptococcus pneumoniae TIGR4 section 109 of 194 of the complete genome 22696 2559.M21.GZ43_(—) AJ414564 gi|15990852|emb|AJ414564.1HSA414564 9.2E−30 375004 Homo sapiens mRNA for connexin40.1 (CX40.1 gene) 22698 2559.N13.GZ43_(—) AL137330 gi|6807822|emp|AL137330.1HSM802010 4.1E−47 375020 Homo sapiens mRNA; cDNA DKFZp434F0272 (from clone DKFZp434F0272) 22714 2560.H01.GZ43_(—) U14567 gi|551536|gb|U14567.1HSU14567 2.7E−42 375248 ***ALU WARNING: Human Alu-J subfamily consensus sequence 22719 2560.K02.GZ43_(—) AF178754.3 gi|7770069|gb|AF178754.3AF178754 3.1E−51 375321 Homo sapiens lithium-sensitive myoinositol monophosphatase A1 (IMPA1) gene, promoter region and p 22720 2560.K08.GZ43_(—) AK009327 gi|12844057|dbj|AK009327.1AK009327 6.3E−80 375327 Mus musculus adult male tongue cDNA, RIKEN full-length enriched library, clone: 2310012P17, full 22721 2560.K10.GZ43_(—) AF344987 gi|13448249|gb|AF344987.1AF344987   1E−300 375329 Hepatitis C virus isolate RDpostSC1c2 polyprotein gene, partial cds 22729 2560.O08.GZ43_(—) AY037285 gi|15982643|gb|AY037285.1AY037284S2 5.2E−54 375423 HIV-1 from Cameroon vpu protein (vpu) and envelope glycoprotein (env) genes, complete cds; and 22732 2561.B03.GZ43_(—) AF035968.2 gi|8714504|gb|AF035968.2AF035968 3.9E−32 376258 Home sapiens integrin alpha 2 (ITGA2) gene, ITGA2-1 allele, exons 6–9, and partial, cds 22733 2561.B12.GZ43_(—) AP000276 gi|4835645|dbj|AP000276.1AP000276 1.9E−27 376267 Homo sapiens genomic DNA, chromosome 21q22.1, D21S226-AML region, clone: 55A9, complete sequence 22750 2561.M09.GZ43_(—) AF052684 gi|2995716|gb|AF052684.1HSPRACAD2 4.1E−41 376528 Homo sapiens protocadherin 43 gene, exon 2 22753 2561.E22.GZ43_(—) AF132952 gi|4680674|gb|AF132952.1AF132952   3E−41 376349 Homo sapiens CGI-18 protein mRNA, complete cds 22754 2561.G20.GZ43_(—) U14573 gi|551542|gb|U14573.1HSU14573 1.5E−71 376395 ***ALU WARNING: Human Alu-Sq subfamily consensus sequence 22755 2561.H17.GZ43_(—) AF052685 gi|2995717|gb|AF052685.1HSPRCAD3 2.1E−24 376416 Homo sapiens protocadherin 43 gene, exon 3, exon 4, and complete cds 22756 2561.I19.GZ43_(—) AF344987 gi|13448249|gb|AF344987.1AF344987 3.2E−201 376442 Hepatitis C virus isolate RDpostsSC1c2 polyprotein gene, partial cds 22761 2561.P16.GZ43_(—) Z78727 gi|1508005|emp|Z78727.1HSPA15B9 1.6E−37 376607 H. sapiens flow-sorted chromosome 6 HindIII fragment, SC6pA15B9 22762 2561.P19.GZ43_(—) U66535 gi|2270915|gb|U66535.1HSITGBF07 8.6E−41 376610 Human beta4-integrin (ITGB4) gene, exons 19, 20, 21, 22, 23, 24 and 25 22763 2561.P23.GZ43_(—) AF167458 gi|6467463|gb|AF167458.1HSDSRPKR04   1E−22 376614 Homo sapiens double stranded RNA activated protein kinase (PKR) gene, intron 1 22771 2456.D04.GZ43_(—) AF307053 gi|12018057|gb|AF307053.1AF307053 0 355904 Thermococcus litoralis sugar kinase, trehalose/maltose binding protein (malE), trehalose/maltose 22777 2456.H02.GZ43_(—) AJ005821 gi|3123571|emb|AJ005821.1HSA5821 5.8E−37 355998 Homo sapiens mRNA for X-like 1 protein 22788 2456.N23.GZ43_(—) AF188746 gi|6425045|gb|AF188746.1AF188746 9.6E−63 356163 Homo sapiens prostrate kallikrein 2 (KLK2) mRNA, complete cds 22796 2457.C19.GZ43_(—) AF368920 gi|14039926|gb|AF368920.1AF368920   1E−47 356279 Caenorhabditis elegans voltage-dependent calcium channel alpha13 subunit (cca-1) mRNA, complete c 22799 2457.D12.GZ43_(—) AK026618 gi|10439509|dbj|AK026618.AK026618 0 356296 Homo sapiens cDNA: FLJ22965 fis, clone KAT10418 22810 2457.H17.GZ43_(—) AE007614 gi|15023883|gb|AE007614.1AE007614   9E−63 356397 Clostridium acetobutylicum ATCC824 section 102 of 356 of the complete genome 22823 2458.A10.GZ43_(—) AK026920 gi|10439892|dbj|AK026920.1AK026920 6.2E−84 356618 Homo sapiens cDNA: FLJ23267 fis, clone COL07266 22827 2458.B23.GZ43_(—) AB050432 gi|10998295|dbj|AB050432.1AB050432 4.3E−129 356655 Macaca fascicularis brain cDNA, clone: QnpA-21861 22829 2458.C06.GZ43_(—) U49973 gi|2226003|gb|U49973.1HSU49973   2E−24 356662 Human Tigger1 transposable element, complete consensus sequence 22842 2458.I09.GZ43_(—) AK023496 gi|10435445|dbj|AK023496.1AK023496 2.4E−39 356809 Homo sapiens cDNA FLJ13434 fis, clone PLACE1002578 22843 2458.I10.GZ43_(—) AF031077 gi|6649934|gb|AF031077.1AF031077 1.3E−52 356810 Homo sapiens chromosome X, cosmid LLNLc110C1837, complete sequence 22845 2458.I17.GZ43_(—) AK026569 gi|10439451|dbj|AK026569.1AK026569 1.8E−38 356817 Homo sapiens cDNA: FLJ22916 fis, clone KAT06406, highly similar to HSCYCR Human mRNA for T-cell 22846 2458.I20.GZ43_(—) AF184614 gi|6983939|gb|AF184614.1AF184614 4.2E−33 356820 Homo sapiens p47-phox (NCF1) gene, complete cds 22855 2458.N06.GZ43_(—) AF367251 gi|14161363|gb|AF367251.1AF367251 2.2E−70 356926 Helicobacter pylori strain CAPM N93 cytotoxin associated protein A (cagA) gene, complete cds 22865 2459.B11.GZ43_(—) AF375597 gi|14150816|gb|AF375597.1AF375596S2 0 357027 Mus musculus medium and short chain L-3- hydroxyacyl-Coenzyme A dehydrogenase (Mschad) gene, exo 22866 2459.C05.GZ43_(—) X04803.2 gi|6647297|emb|X04803.2HSYUBG1 6.4E−52 357045 Homo sapiens ubiquitin gene 22873 2459.F20.GZ43_(—) AK025207 gi|10437672|dbj|AK025207.1AK025207 0 357132 Homo sapiens cDNA: FLJ21554 fis, clone COL06330 22877 2459.H09.GZ43_(—) AB046623 gi|9651056|dbj|AB046623.1AB046623 1.7E−35 357169 Macaca fascicularis brain cDNA, clone QccE-10576 22888 2459.O23.GZ43_(—) AL049301 gi|4500067|emb|AL049301.1HSM800086 1.3E−31 357351 Homo sapiens mRNA; cDNA DKFZp564P073 (from clone DKFZp564P073) 22889 2459.P24.GZ43_(—) AK018110 gi|12857675|dbj|AK018110.1AK018110 1.5E−33 357376 Mus musculus adult male medulla oblongata cDNA, RIKEN full-length enriched library, clone: 633040 22903 2464.H22.GZ43_(—) AB035344 gi|8176599|dbj|AB035344.1AB035344S1 1.1E−127 357870 Homo sapiens TCL6 gene, exon 1–10b 22904 2464.I04.GZ43_(—) AK025125 gi|10437578|dbj|AK025125.1AK025125 0 357876 Homo sapiens cDNA: FLJ21472 fis, clone COL04936 22905 2464.I20.GZ43_(—) AK025966 gi|10438647|dbj|AK025966.1AK025966 2.8E−61 357892 Homo sapiens cDNA: FLJ22313 fis, clone HRC05216 22909 2464.K18.GZ43_(—) AF287938 gi|12656333|gb|AF287938.1AF287938 8.3E−44 357938 Guichenotia ledifolia NADH dehydrogenase subunit F (ndhF) gene, partial cds; chloroplast gene for 22912 2464.L15.GZ43_(—) AF141308 gi|5737754|gb|AF141308.1HSPMFG1 9.9E−76 357959 Homo sapiens polyamine modulated factor-1 (PMF1) gene, exon 1 22918 2464.P17.GZ43_(—) AF052684 gi|2995716|gb|AF052684.1HSPRCAD2   3E−29 358057 Homo sapiens protocadherin 43 gene, exon 2 22934 2465.J19.GZ43_(—) X02571 gi|31870|emb|X02571.1HSGP5MOS 2.7E−48 358299 Human gene fragment related to oncogene c-mos with Alu repeats (locus gp5, region NV-1) 22935 2465.K20.GZ43_(—) AK019509 gi|12859761|dbj|AK019509.1AK019509 2.5E−63 358324 Mus musculus 0 day neonate skin cDNA, RIKEN full-length enriched library, clone: 4632435C11, full 22937 2465.L06.GZ43_(—) AK009327 gi|12844057|dbj|AK009327.1AK009327 7.9E−73 358334 Mus musculus adult male tongue cDNA, RIKEN full-length enriched library, clone: 2310012P17, full 22939 2465.M11.GZ43_(—) AK022253 gi|10433611|dbj|AK022253.1AK022253 1.4E−112 358363 Homo sapiens cDNA FLJ12191 fis, clone MAMMA1000843 22943 2466.B02.GZ43_(—) AK023055 gi|10434796|dbj|AK023055.1AK023055 7.5E−39 360107 Homo sapiens cDNA FLJ12993 fis, clone NT2RP3000197 22944 2466.C15.GZ43_(—) AB013897 gi|6177784|dbj|AB013897.1AB013897 4.3E−53 360144 Homo sapiens mRNA for HKR1, partial cds 22945 2466.D19.GZ43_(—) AL050141 gi|4884352|emb|AL050141.1HSM800441 3.4E−110 360172 Homo sapiens mRNA; cDNA DKFZp586O031 (from clone DKFZp586O031) 22952 2466.I08.GZ43_(—) AJ271729 gi|6900103|emb|AJ271729.1HSA271729 6.2E−72 360281 Homo sapiens mRNA for glucose-regulated protein (HSPA5 gene) 22953 2466.J01.GZ43_(—) AY058527 gi|16197970|gb|AY058527.1 Drosophila 9.4E−40 360298 melanogaster LD23445 full length cDNA 22954 2466.J24.GZ43_(—) AF331425 gi|13375486|gb|AF331425.1AF331425 1.6E−77 360321 HIV-1 D311 from Australia envelope protein (env) gene, partial cds 22958 2467.B24.GZ43_(—) AJ005821 gi|3123571|emb|AJ005821.1HSA5821 1.4E−34 360513 Homo sapiens mRNA for X-like 1 protein 22963 2467.H18.GZ43_(—) AF036235 gi|2695679|gb|AF036235.1AF036235   2E−169 360651 Gorilla gorilla L1 retrotransposon L1Gg- 1A, complete sequence 22964 2467.A03.GZ43_(—) BC012960 gi|5277963|gb|BC012960.1BC012960 8.7E−36 360468 Mus musculus, ring finger protein 12, clone MGC: 13712 IMAGE: 4193003, mRNA, complete cds 22965 2467.A05.GZ43_(—) BC009113 gi|14318629|gb|BC009113.1BC009113 4.1E−167 360470 Homo sapiens, clone MGC: 18122 IMAGE: 4153377, mRNA, complete cds 22969 2467.G01.GZ43_(—) U14573 gi|551542|gb|U14573.1HSU14573   2E−61 360610 ***ALU WARNING: Human Alu-Sq subfamily consensus sequence 22971 2467.N22.GZ43_(—) AF117756 gi|4530440|gb|AF117756.1AF117756 6.8E−77 360799 Homo sapiens thyroid hormone receptor- associated protein complex component TRAP150 mRNA, complete 22973 2467.I12.GZ43_(—) AK024049 gi|10436318|dbj|AK024049.1AK024049 2.1E−47 360669 Homo sapiens cDNA FLJ13987 fis, clone Y79AA1001963, weakly similar to PUTATIVE PRE-MRNA SPLICING 22977 2467.K14.GZ43_(—) AB030001 gi|7416074|dbj|AB030001.1AB030001 7.2E−22 360719 Homo sapiens gene for SGRF, complete cds 22979 2467.N03.GZ43_(—) AK023448 gi|10435386|dbj|AK023448.1AK023448 0 360780 Homo sapiens cDNA FLJ13386 fis, clone PLACE1001104, weakly similar to MYOSIN HEAVY CHAIN, NON-MU 22980 2467.N07.GZ43_(—) AK001931 gi|7023502|dbj|AK001931.1AK001931 2.3E−54 360784 Homo sapiens cDNA FLJ11069 fis, clone PLACE1004930, highly similar to Homo sapiens MDC-3.13 isofo 22981 2467.N09.GZ43_(—) AE008338 gi|15159908|gb|AE008338.1AE008338 3.7E−50 360786 Agrobacterium tumefaciens strain C58 linear chromosome, section 142 of 187 of the complete sequen 22986 2472.C18.GZ43_(—) K01921 gi|339606|gb|K01921.1HUMTGNB   3E−29 360915 Human Asn-tRNA gene, clone pHt6-2, complete sequence and flanks 22992 2472.G03.GZ43_(—) AF321082 gi|12958576|gb|AF321082.1AF321082 5.1E−28 360996 HIV-1 isolate DGOB from France envelope glycoprotein (env) gene, complete cds 22999 2472.M22.GZ43_(—) AF338299 gi|12958808|gb|AF338299.1AF338299 1.4E−145 361159 Amazona ochrocephala auropalliata mitochondrial control region 1, partial sequence 23002 2472.P22.GZ43_(—) AJ330257 gi|15874675|emb|AJ330257.1HSA330257 1.1E−63 361231 Homo sapiens genomic sequence surrounding NotI site, clone NL1-FA14R 23005 2473.F08.GZ43_(—) AF306355 gi|14573206|gb|AF306355.1AF306355 3.2E−29 361361 Homo sapiens clone TF3.19 immunoglobulin heavy chain variable region mRNA, partial cds 23006 2473.F14.GZ43_(—) AB050477 gi|11034759|dbj|AB050477.1AB050477 0 361367 Homo sapiens NIBAN mRNA, complete cds 23011 2473.I08.GZ43_(—) AF224341 gi|15982934|gb|AF224341.1AF224341 8.7E−67 361433 Mus musculus thiamine transporter 1 (S1c19a2) gene, exons 1 through 6 and complete cds 23015 2473.O13.GZ43_(—) AF203815 gi|6979641|gb|AF203815.1AF203815 5.4E−44 361582 Homo sapiens alpha gene sequence 23018 2474.C08.GZ43_(—) AK000373 gi|7020417|dbj|AK000373.1AK000373 5.6E−47 361673 Homo sapiens cDNA FLJ20366 fis, clone HEP18008 23021 2474.G17.GZ43_(—) U75285 gi|2315862|gb|U75285.1HSU75285 Homo 1.1E−87 361778 sapiens apoptosis inhibitor survivin gene, complete cds 23023 2474.I06.GZ43_(—) Z81315 gi|1644298|emb|Z81315.1HSF62D4 2.1E−67 361815 Human DNA sequence from fosmid F62D4 on chromosome 22q12–qter 23024 2474.J18.GZ43_(—) AF029062 gi|3712662|gb|AF029062.1AF029062 1.2E−28 361851 Homo sapiens DEAD-box protein (BAT1) gene, partial cds 23030 2474.P22.GZ43_(—) AL050204 gi|4884443|emb|AL050204.1HSM800501 8.9E−33 361999 Homo sapiens mRNA; cDNA DKFZp586F1223 (from clone DKFZp586F1223) 23031 2475.A05.GZ43_(—) AL109666 gi|5689800|emb|AL109666.1IRO35907 6.3E−43 362006 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 35907 23032 2475.C18.GZ43_(—) AK023739 gi|10435762|dbj|AK023739.1AK023739 2.8E−180 362067 Homo sapiens cDNA FLJ13677 fis, clone PLACE1011982 23033 2475.E18.GZ43_(—) AK024206 gi|10436527|dbj|AK024206.1AK024206 1.9E−21 362115 Homo sapiens cDNA FLJ14144 fis, clone MAMMA1002909 23035 2475.H06.GZ43_(—) AF322634 gi|12657820|gb|AF322634.1AF322634S1 1.2E−173 362175 Human herpesvirus 3 strain VZV-Iceland glycoprotein B gene, complete cds 23036 2475.H13.GZ43_(—) AF026853 gi|3882436|gb|AF026853.1HSHADHSC 1 2.1E−30 362182 Homo sapiens mitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC) gene, nuclear 23039 2475.N08.GZ43_(—) AK011295 gi|12847322|dbj|AK011295.1AK011295 1.1E−84 362321 Mus musculus 10 days embryo cDNA, RIKEN full-length enriched library, clone: 2610002L04, full ins 23045 2475.M20.GZ43_(—) AK023843 gi|10435902|dbj|AK023843.1AK023843 8.8E−42 362309 Homo sapiens cDNA FLJ13781 fis, clone PLACE4000465 23046 2475.N21.GZ43_(—) S45332 gi|255496|gb|S45332.1S45332 1.4E−101 362334 erythropoietin receptor [human, placental, Genomic, 8647 nt] 23055 2480.G11.GZ43_(—) X83497 gi|603558|emb|X83497.1HSLTRERV9 6.1E−40 358658 H. sapiens DNA for ZNF80-linked ERV9 long terminal repeat 23056 2480.H06.GZ43_(—) AB002070 gi|12862447|dbj|AB002070.1AB002070 5.5E−28 358677 Aspergillus clavatus gene for 18S rRNA, partial sequence, strain: NRRL 1 23061 2480.M20.GZ43_(—) AL1576971 gi|11121002|emb|AL157697.11AL157697 9.3E−36 358811 Human DNA sequence from clone RP5- 1092C14 on chromosome 6, complete sequence [Homo sapiens] 23064 2480.P23.GZ43_(—) AB037719 gi|7242950|dbj|AB037719.1AB037719 3.6E−35 358886 Homo sapiens mRNA for KIAA1298 protein, partial cds 23065 2481.B06.GZ43_(—) AK023471 gi|10435415|dbj|AK023471.1AK023471 0 358917 Homo sapiens cDNA FLJ13409 fis, clone PLACE1001716 23068 2481.D10.GZ43_(—) AL021306 gi|2808416|emb|AL021306.1HS1109B5   7E−52 358969 Human DNA sequence from clone CTB- 1109B5 on chromosome 22 Contains a GSS, complete sequence [Homo 23069 2481.D13.GZ43_(—) X64467 gi|28579|emb|X64467.1HSALADG 4.2E−53 358972 H. sapiens ALAD gene for porphobilinogen synthase 23075 2481.K12.GZ43_(—) AK026901 gi|10439868|dbj|AK026901.1AK026901 5.9E−52 359139 Homo sapiens cDNA: FLJ23248 fis, clone COL03555 23083 2482.E17.GZ43_(—) AK022821 gi|10434440|dbj|AK022821.1AK022821 9.4E−35 359384 Homo sapiens cDNA FLJ12759 fis, clone NT2RP2001347 23084 2482.E20.GZ43_(—) AK014328 gi|12852104|dbj|AK014328.1AK014328 5.2E−99 359387 Mus musculus 14, 17 days embryo head cDNA, RIKEN full-length enriched library, clone: 3230401M21, 23091 2482.N09.GZ43_(—) AE008514 gi|15459095|gb|AE008514.1AE008514 6.9E−107 359592 Streptococcus pneumoniae R6 section 130 of 184 of the complete genome 23100 2483.J07.GZ43_(—) AK022722 gi|10434285|dbj|AK022722.1AK022722   1E−300 359878 Homo sapiens cDNA FLJ12660 fis, clone NT2RM4002174, moderately similar to MRP PROTEIN 23101 2483.K02.GZ43_(—) AK012908 gi|12849956|dbj|AK012908.1AK012908 3.7E−189 359897 Mus musculus 10, 11 days embryo cDNA, RIKEN full-length enriched library, clone: 2810046L04, full 23106 2483.O07.GZ43_(—) AK014328 gi|12852104|dbj|AK014328.1AK014328 3.2E−103 359998 Mus musculus 14, 17 days embryo head cDNA, RIKEN full-length enriched library, clone: 3230401M21, 23108 2488.C19.GZ43_(—) AB023199 gi|4589607|dbj|AB023199.1AB023199 1.1E−50 362511 Homo sapiens mRNA for KIAA0982 protein, complete cds 23110 2488.E20.GZ43_(—) AK001136 gi|7022203|dbj|AK001136.1AK001136   1E−35 362560 Homo sapiens cDNA FLJ10274 fis, clone HEMBB1001169 23111 2488.F06.GZ43_(—) AK011295 gi|12847322|dbj|AK011295.1AK011295 8.1E−55 362570 Mus musculus 10 days embryo cDNA, RIKEN full-length enriched library, clone: 2610002L04, full ins 23113 2488.G02.GZ43_(—) X15723 gi|31481|emb|X15723.1HSFURIN Human 1.8E−85 362590 fur gene, exons 1 through 8 23117 2488.K04.GZ43_(—) AF026853 gi|3882436|gb|AF026853.1HSHADHSC 1 2.1E−30 362688 Homo sapiens mitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC) gene, nuclear 23122 2489.A03.GZ43_(—) AB050477 gi|11034759|dbj|AB050477.1AB050477 6.7E−46 362831 Homo sapiens NIBAN mRNA, complete cds 23124 2489.A13.GZ43_(—) AK026618 gi|10439509|dbj|AK026618.1AK026618 1.8E−178 362841 Homo sapiens cDNA: FLJ22965 fis, clone KAT10418 23127 2489.D18.GZ43_(—) AF086310 gi|3483655|gb|AF086310.1HUMZD51F08 2.5E−79 362918 Homo sapiens full length insert cDNA clone ZD51F08 23128 2489.F09.GZ43_(—) AF271388 gi|8515842|gb|AF271388.1AF271388 0 362957 Homo sapiens CMP-N-acetylneuraminic acid synthase mRNA, complete cds 23129 2489.G05.GZ43_(—) AK023739 gi|10435762|dbj|AK023739.1AK023739 6.8E−209 362977 Homo sapiens cDNA FLJ13677 fis, clone PLACE1011982 23140 2489.M11.GZ43_(—) AE008029 gi|15155994|gb|AE008029.1AE008029 4.2E−44 363127 Agrobacterium tumefaciens strain C58 circular chromosome, section 87 of 254 of the complete seque 23144 2490.B06.GZ43_(—) AK001915 gi|7023475|dbj|AK001915.1AK001915 1.7E−43 363242 Homo sapiens cDNA FLJ11053 fis, clone PLACE1004664 23155 2490.J22.GZ43_(—) AF026853 gi|3882436|gb|AF026853.1HSHADHSC 1   2E−30 363450 Homo sapiens mitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC) gene, nuclear 23160 2490.N24.GZ43_(—) AF167438 gi|9622123|gb|AF167438.1AF167438 8.8E−74 363548 Homo sapiens androgen-regulated short- chain dehydrogenase/reductase 1 (ARSDR1) mRNA, complete cds 23163 2491.C13.GZ43_(—) AK022338 gi|10433714|dbj|AK022338.1AK022338 6.2E−30 363657 Homo sapiens cDNA FLJ12276 fis, clone MAMMA1001692 23174 2491.P10.GZ43_(—) AJ276936 gi|12214232|emb|AJ276936.1NME276936 0 363966 Neisseria meningitidis partial tbpB gene for transferrin binding protein B subunit, allele 66, 23175 2491.P20.GZ43_(—) AY027632 gi|15418751|gb|AY027632.1 Measles 7.8E−283 363976 virus strain MVs/Masan.KOR/49.00/2 hemagglutinin (H) mRNA, complete cds 23177 2496.C08.GZ43_(—) U67829 gi|2289943|gb|U67829.1HSU67829 3.6E−90 364139 Human primary Alu transcript 23181 2496.F14.GZ43_(—) X16983 gi|33945|emb|X16983.1HSINTAL4 4.7E−53 364217 Human mRNA for integrin alpha-4 subunit 23183 2496.I06.GZ43_(—) BC004138 gi|13278716|gb|BC004138.1BC004138 8.3E−53 364281 Homo sapiens, ribosomal protein L6, clone MGC: 1635 IMAGE: 2823733, mRNA, complete cds 23184 2496.K15.GZ43_(—) NM_024711 gi|13376008|ref|NM_024711.1 Homo 1.1E−28 364338 sapiens hypothetical protein FLJ22690 (FLJ22690), mRNA 23192 2497.E09.GZ43_(—) AF284421 gi|15088516|gb|AF284421.1AF284421 4.1E−158 364572 Homo sapiens complement factor MASP-3 mRNA, complete cds 23195 2497.J05.GZ43_(—) Z56298 gi|1027529|emb|Z56298.1HS10C4R 2.5E−42 364688 H. sapiens CpG island DNA genomic Mse1 fragment, clone 10c4, reverse read cpg10c4.rt1a 23199 2497.L05.GZ43_(—) AK023448 gi|10435386|dbj|AK023448.1AK023448 0 364736 Homo sapiens cDNA FLJ13386 fis, clone PLACE1001104, weakly similar to MYOSIN HEAVY CHAIN, NON-MU 23207 2562.B09.GZ43_(—) M64241 gi|190813|gb|M64241.1HUMQM Human 3.2E−52 375496 Wilm's tumor-related protein (QM) mRNA, complete cds 23210 2562.I01.GZ43_(—) AF083247 gi|5106788|gb|AF083247.1AF083247 2.4E−48 375656 Homo sapiens MDG1 mRNA, complete cds 23214 2562.O01.GZ43_(—) AF223389 gi|11066459|gb|AF223389.1AF223389 8.7E−57 375800 Homo sapiens PCGEM1 gene, non-coding mRNA 23217 2562.H11.GZ43_(—) AK023442 gi|10435378|dbj|AK023442.1AK023442 1.7E−64 375642 Homo sapiens cDNA FLJ13380 fis, clone PLACE1001007 23218 2562.B24.GZ43_(—) AF287932 gi|12656321|gb|AF287932.1AF287932 1.8E−31 375511 Rayleya bahiensis NADH dehydrogenase subunit F (ndhF) gene, partial cds; chloroplast gene for chl 23229 2498.A02.GZ43_(—) AY031766 gi|13738569|gb|AY031766.1 HIV-1 isolate 1.3E−29 364853 NC5203-1999 from USA pol polyprotein (pol) gene, partial cds 23230 2498.A19.GZ43_(—) AL122114 gi|6102936|emb|AL122114.1HSM801274   1E−59 364870 Homo sapiens mRNA; cDNA DKFZp434K0221 (from clone DKFZp434K0221); partial cds 23235 2498.G15.GZ43_(—) M86752 gi|184564|gb|M86752.1HUMIEF Human 3.4E−54 365010 transformation-sensitive protein (IEF SSP 3521) mRNA, complete cds 23238 2498.I17.GZ43_(—) AJ335654 gi|15880072|emb|AJ335654.1HSA335654 4.3E−41 365060 Homo sapiens genomic sequence surrounding NotI site, clone NR5-IJ21R 23239 2498.K20.GZ43_(—) X15940 gi|36129|emb|X15940.1HSRPL31 Human 1.7E−25 365111 mRNA for ribosomal protein L31 23240 2498.M19.GZ43_(—) AF203815 gi|6979641|gb|AF203815.1AF203815   4E−47 365158 Homo sapiens alpha gene sequence 23242 2498.P07.GZ43_(—) AF410975 gi|15553753|gb|AF410975.1AF410975 3.5E−29 365218 Measles virus genotype D4 strain MVi/Montreal.CAN/12.89 hemagglutinin gene, complete cds 23244 2507.C03.GZ43_(—) NM_025080 gi|13376633|ref|NM_025080.1 Homo   1E−232 366992 sapiens hypothetical protein FLJ22316 (FLJ22316), mRNA 23259 2511.J18.GZ43_(—) M81806 gi|184406|gb|M81806.1HUMHSKPQZ7 4.7E−34 369643 Human housekeeping (Q1Z 7F5) gene, exons 2 through 7, complete cds 23261 2499.A22.GZ43_(—) AK024860 gi|10437268|dbj|AK024860.1AK024860 6.4E−49 365257 Homo sapiens cDNA: FLJ21207 fis, clone COL00362 23263 2499.C09.GZ43_(—) AJ330464 gi|15874882|emb|AJ330464.1HSA330464 3.3E−100 365292 Homo sapiens genomic sequence surrounding NotI site, clone NR1-IL7C 23268 Clu1009284.1 AF026853 gi|3882436|gb|AF026853.1HSHADHSC 1 1.3E−30 Homo sapiens mitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC) gene, nuclear 23269 Clu1022935.2 AL590711.7 gi|16304966|emb|AL590711.7AL590711 3.9E−118 Human DNA sequence from clone RP11- 284O18 on chromosome 9, complete sequence [Homo sapiens] 23270 Clu1037152.1 M87652 gi|182743|gb|M87652.1HUMFPRPR 1.1E−21 Human formylpeptide receptor gene, promoter region 23271 Clu13903.1 AK026618 gi|10439509|dbj|AK026618.1AK026618 1.5E−293 Homo sapiens cDNA: FLJ22965 fis, clone KAT10418 23272 Clu139979.2 AB056828 gi|13365953|dbj|AB056828.1AB056828 1.4E−33 Macaca fascicularis brain cDNA clone: QflA-13447, full insert sequence 23274 Clu187860.2 AL050204 gi|4884443|emb|AL050204.1HSM800501 4.7E−33 Homo sapiens mRNA; cDNA DKFZp586F1223 (from clone DKFZp586F1223) 23275 Clu189993.1 AB030001 gi|7416074|dbj|AB030001.1AB030001 9.6E−87 Homo sapiens gene for SGRF, complete cds 23276 Clu20975.1 AF039687 gi|3170173|gb|AF039687.1AF039687 2.7E−190 Homo sapiens antigen NY-CO-1 (NY-CO-) 1) mRNA, complete cds 23278 Clu218833.1 AF223389 gi|11066459|gb|AF223389.1AF223389   1E−139 Homo sapiens PCGEM1 gene, non-coding mRNA 23279 Clu244504.2 Z59663 gi|1031576|emb|Z59663.1HS168F9F 7.5E−22 H. sapiens CpG island DNA genomic Mse1 fragment, clone 168f9, forward read cpg168f9.ft1a 23281 Clu376516.1 AK018003 gi|12857525|dbj|AK018003.1AK018003 1.7E−63 Mus musculus adult male thymus cDNA, RIKEN full-length enriched library, clone: 5830450H20, full 23282 Clu376630.1 U93571 gi|2072968|gb|U93571.1HSU93571 8.7E−291 Human L1 element L1.24 p40 gene, complete cds 23283 Clu377044.2 AK024860 gi|10437268|dbj|AK024860.1AK024860 1.6E−49 Homo sapiens cDNA: FLJ21207 fis, clone COL00362 23284 Clu379689.1 BC007110 gi|13937991|gb|BC007110.1BC007110 0 Homo sapiens, clone MGC: 14768 IMAGE: 4291902, mRNA, complete cds 23286 Clu387530.4 AK009770 gi|12844769|dbj|AK009770.1AK009770 1.5E−80 Mus musculus adult male tongue cDNA, RIKEN full-length enriched library, clone: 2310043C14, full 23287 Clu388450.2 AK023448 gi|10435386|dbj|AK023448.1AK023448 0 Homo sapiens cDNA FLJ13386 fis, clone PLACE1001104, weakly similar to MYOSIN HEAVY CHAIN, NON-MU 23288 Clu396325.1 Z78727 gi|1508005|emb|Z78727.1HSPA15B9 1.2E−38 H. sapiens flow-sorted chromosome 6 HindIII fragment, SC6pA15B9 23291 Clu400258.1 AB038971 gi|12862672|dbj|AB038971.1AB038965S7   4E−74 Homo sapiens CFLAR gene, exon 10, exon 11 23293 Clu402591.3 AF170811 gi|6715105|gb|AF170811.AF170811   7E−26 Homo sapiens CaBP2 (CABP2) gene, complete cds 23295 Clu404081.2 AK011443 gi|12847570|dbj|AK011443.1AK011443   5E−153 Mus musculus 10 days embryo cDNA, RIKEN full-length enriched library, clone: 2610018B07, full ins 23297 Clu41346.1 AB042029 gi|16326128|dbj|AB042029.1AB042029 0 Homo sapiens DEPC-1 mRNA for prostate cancer antigen-1, complete cds 23299 Clu416124.1 AK000293 gi|7020278|dbj|AK000293.1AK000293 3.3E−34 Homo sapiens cDNA FLJ20286 fis, clone HEP04358 23300 Clu417672.1 AK027667 gi|14042514|dbj|AK027667.1AK027667 1.6E−183 Homo sapiens cDNA FLJ14761 fis, clone NT2RP3003302 23301 Clu423664.1 AF287270 gi|9844925|gb|AF287270.1AF287270 6.3E−34 Homo sapiens mucolipin (MCOLN1) gene, complete cds 23303 Clu442923.3 BC014256 gi|15559816|gb|BC014256.1BC014256 1.5E−236 Homo sapiens, Similar to guanine nucleotide binding protein (G protein), beta polypeptide 2-like 23304 Clu446975.1 AL022342.6 gi|7159715|emb|AL022342.6HS29M10 1.8E−74 Human DNA sequence from clone RP1- 29M10 on chromosome 20, complete sequence [Homo sapiens] 23305 Clu449839.2 BC001607 gi|12804410|gb|BC001607.1BC001607 1.9E−27 Homo sapiens, clone IMAGE: 3543874, mRNA, partial cds 23306 Clu449889.1 S45332 gi|255496|gb|S45332.1S45332   8E−101 erythropoietin receptor [human, placental, Genomic, 8647 nt] 23307 Clu451707.2 AJ004862 gi|4038586|emb|AJ004862.1HSAJ4862 4.7E−49 Homo sapiens partial MUC5B gene, exon 1–29 23308 Clu454509.3 AK022973 gi|10434673|dbj|AK022973.1AK022973 1.7E−285 Homo sapiens cDNA FLJ12911 fis, clone NT2RP2004425, highly similar to Mus musculus axotrophin mR 23310 Clu455862.1 AK023951 gi|10436049|dbj|AK023951.1AK023951 3.3E−27 Homo sapiens cDNA FLJ13889 fis, clone THYRO1001595 23311 Clu460493.1 AK012865 gi|12849888|dbj|AK012865.1AK012865 1.7E−57 Mus musculus 10, 11 days embryo cDNA, RIKEN full-length enriched library, clone: 2810036K01, full 23314 Clu470032.1 AF223389 gi|11066459|gb|AF223389.1AF223389 1.2E−116 Homo sapiens PCGEM1 gene, non-coding mRNA 23317 Clu477271.1 BC007307 gi|13938350|gb|BC007307.1BC007307 4.6E−56 Homo sapiens, Similar to zinc finger protein 268, clone IMAGE: 3352268, mRNA, partial cds 23318 Clu480410.1 AK000713 gi|7020973|dbj|AK000713.1AK000713 0 Homo sapiens cDNA FLJ20706 fis, clone KAIA1273 23320 Clu497138.1 AF270579 gi|9755121|gb|AF270579.1AF270579 3.8E−29 Homo sapiens clone 18ptel_481c6 sequence 23321 Clu498886.1 U49973 gi|2226003|gb|U49973.1HSU49973 1.4E−24 Human Tigger1 transposable element, complete consensus sequence 23323 Clu5013.2 BC007458 gi|13938610|gb|BC007458.1BC007458 0 Homo sapiens, clone MGC: 12217 IMAGE: 3828631, mRNA, complete cds 23324 Clu5105.2 AL512712 gi|12224956|emb|AL512712.1HSM80291 0 5 Homo sapiens mRNA; cDNA DKFZp761J139 (from clone DKFZp761J139) 23325 Clu510539.2 AK023812 gi|10435860|dbj|AK023812.1AK023812 1.4E−32 Homo sapiens cDNA FLJ13750 fis, clone PLACE3000331 23326 Clu514044.1 AJ403947 gi|14270388|emb|AJ403947.1HSA403947 4.4E−295 Homo sapiens partial SLC22A3 gene for organic cation transporter 3, exon 2 23329 Clu520370.1 AF093016 gi|5579305|gb|AF093016.1AF093016 7.3E−67 Homo sapiens 22k48 gene, 5′UTR 23330 Clu524917.1 AL1573620 gi|15028613|emb|AL157362.10AL157362 4.9E−23 Human DNA sequence from clone RP11- 142D16 on chromosome 13q14.3–21.31, complete sequence [Homo 23331 Clu528957.1 AB060919 gi|13874604|dbj|AB060919.1AB060919 1.5E−31 Macaca fascicularis brain cDNA clone: QtrA-14728, full insert sequence 23334 Clu540142.2 AJ005821 gi|3123571|emb|AJ005821.1HSA5821 3.5E−36 Homo sapiens mRNA for X-like 1 protein 23335 Clu540379.2 AF088011 gi|3523217|gb|AF088011.1HUMYY75G10 2.4E−49 Homo sapiens full length insert cDNA clone YY75G10 23336 Clu549507.1 U14571 gi|551540|gb|U14571.1HSU14571 1.6E−48 ***ALU WARNING: Human Alu-Sc subfamily consensus sequence 23339 Clu556827.3 AB038163 gi|10280537|dbj|AB038163.1AB038163 9.7E−22 Homo sapiens NDUFV3 gene for mitochondrial NADH-Ubiquinone oxidoreductase, complete cds 23340 Clu558569.2 AF061258 gi|3108092|gb|AF061258.1AF061258   1E−300 Homo sapiens LIM protein mRNA, complete cds 23343 Clu570804.1 AK023843 gi|10435902|dbj|AK023843.1AK023843 4.4E−42 Homo sapiens cDNA FLJ13781 fis, clone PLACE4000465 23344 Clu572170.2 U18271 gi|885681|gb|U18271.1HSTMPO6 Human 4.9E−57 thymopoietin (TMPO) gene, partial exon 6, complete exon 7, partial exon 8, and partial cds for t 23346 Clu587168.1 AJ276804 gi|10803412|emb|AJ276804.1HSA276804 5.8E−69 Homo sapiens mRNA for protocadherin (PCDHX gene) 23347 Clu588996.1 U73166 gi|1613889|gb|U73166.1U73166 Homo 9.3E−22 sapiens cosmid clone LUCA15 from 3p21.3, complete sequence 23349 Clu598388.1 AF327178 gi|11878341|gb|AF327178.1AF327178 1.1E−26 Homo sapiens clone 20ptel_cA35_21t7 sequence 23350 Clu604822.2 AB063021 gi|14388457|dbj|AB063021.1AB063021 2.6E−65 Macaca fascicularis brain cDNA clone: QmoA-11389, full insert sequence 23353 Clu627263.1 AK021759 gi|10433005|dbj|AK021759.1AK021759 5.7E−30 Homo sapiens cDNA FLJ11697 fis, clone HEMBA1005035 23356 Clu641662.2 AL1576971 gi|11121002|emb|AL157697.11AL157697   7E−84 Human DNA sequence from clone RP5- 1092C14 on chromosome 6, complete sequence [Homo sapiens] 23358 Clu6712.1 AK024029 gi|10436287|dbj|AK024029.1AK024029 0 Homo sapiens cDNA FLJ13967 fis, clone Y79AA1001402, weakly similar to Homo sapiens paraneoplasti 23361 Clu685244.2 S56773 gi|298606|gb|S56773.1S56773 putative 1.1E−35 serine-threonine protein kinase {3′ UTR, Alu repeats} [human, Genomic, 1470 nt] 23362 Clu691653.1 D28126 gi|559316|dbj|D28126.1HUMATPSAS 6.3E−37 Human gene for ATP synthase alpha subunit, complete cds (exon 1 to 12) 23367 Clu709796.2 AB070013 gi|15207866|dbj|AB070013.1AB070013 8.4E−118 Macaca fascicularis testis cDNA clone: QtsA-11243, full insert sequence 23369 Clu727966.1 AF271388 gi|8515842|gb|AF271388.1AF271388 0 Homo sapiens CMP-N-acetylneuraminic acid synthase mRNA, complete cds 23372 Clu756337.1 BC004923 gi|13436241|gb|BC004923.1BC004923 4.1E−250 Homo sapiens, clone IMAGE: 3605104, mRNA, partial cds 23376 Clu823296.3 AK023179 gi|10434987|dbj|AK023179.1AK023179 6.4E−33 Homo sapiens cDNA FLJ13117 fis, clone NT2RP3002660 23377 Clu830453.2 AK027301 gi|14041890|dbj|AK027301.1AK027301 0 Homo sapiens cDNA FLJ14395 fis, clone HEMBA1003250, weakly similar to PROTEIN KINASE APK1A (EC 2 23378 Clu839006.1 AB023199 gi|4589607|dbj|AB023199.1AB023199 3.3E−51 Homo sapiens mRNA for KIAA0982 protein, complete cds 23379 Clu847088.1 AL078632.6 gi|6002309|emb|AL078632.6HSA255N20 4.2E−40 Human DNA sequence from clone 255N20 on chromosome 22, complete sequence [Homo sapiens] 23380 Clu853371.2 S79349 gi|1110571|gb|S79349.1S79349 Homo 1.6E−48 sapiens type 1 iodothyronine deiodinase (hdiol) gene, partial cds 23381 Clu88462.1 AF026855 gi|3882438|gb|AF026855.1HSHADHSC 3 1.1E−65 Homo sapiens mitochondrial short-chain L- 3-hydroxyacyl-CoA dehydrogenase (HADHSC) gene, nuclear 23382 Clu935908.2 AK025271 gi|10437753|dbj|AK025271.1AK025271 8.2E−54 Homo sapiens cDNA: FLJ21618 fis, clone COL07487 23386 DTT00087024.1 AF036235 gi|2695679|gb|AF036235.1AF036235 0 Gorilla gorilla L1 retrotransposon L1Gg- 1A, complete sequence 23387 DTT00089020.1 AF324172 gi|12958747|gb|AF324172.1AF324172 1.1E−142 Dictyophora indusiata strain ASI 32001 internal transcribed spacer 1, partial sequence; 5.8S ribo 23388 DTT00171014.1 AB050477 gi|11034759|dbj|AB050477.1AB050477 0 Homo sapiens NIBAN mRNA, complete cds 23389 DTT00514029.1 BC001978 gi|12805042|gb|BC001978.1BC001978   6E−284 Homo sapiens, clone IMAGE: 3461487, mRNA, partial cds 23390 DTT00740010.1 AF216292 gi|7229461|gb|AF216292.1AF216292 9.5E−229 Homo sapiens endoplasmic reticulum lumenal Ca2+ binding protein grp78 mRNA, complete cds 23391 DTT00945030.1 AL117237 gi|5834563|emb|AL117237.1HS328E191 0 Novel human gene mapping to chomosome 1 23394 DTT01315010.1 X16983 gi|33945|emb|X16983.1HSINTAL4 0 Human mRNA for integrin alpha-4 subunit 23395 DTT01503016.1 AK025473 gi|10437996|dbj|AK025473.1AK025473 0 Homo sapiens cDNA: FLJ21820 fis, clone HEP01232 23396 DTT01555018.1 AE007613 gi|15023874|gb|AE007613.1AE007613 0 Clostridium acetobutylicum ATCC824 section 101 of 356 of the complete genome 23397 DTT01685047.1 M54985 gi|177005|gb|M54985.1GIBBGLOETAH. 6.8E−107 lar psi-eta beta-like globin pseudogene, exon 1, 2, 3 23398 DTT01764019.1 AF307053 gi|12018057|gb|AF307053.1AF307053 0 Thermococcus litoralis sugar kinase, trehalose/maltose binding protein (malE), trehalose/maltose 23401 DTT02367007.1 AK001580 gi|7022920|dbj|AK001580.1AK001580 0 Homo sapiens cDNA FLJ10718 fis, clone NT2RP3001096, weakly similar to Rattus norvegicus leprecan 23402 DTT02671007.1 AF384048 gi|14488027|gb|AF384048.1AF384048 1.8E−170 Homo sapiens interferon kappa precursor gene, complete cds 23403 DTT02737017.1 AF182418 gi|10197635|gb|AF182418.1AF182418   9E−207 Homo sapiens MDS017 (MDS017) mRNA, complete cds 23404 DTT02850005.1 AK011295 gi|12847322|dbj|AK011295.1AK011295 2.5E−141 Mus musculus 10 days embryo cDNA, RIKEN full-length enriched library, clone: 2610002L04, full ins 23406 DTT03037029.1 AE006916 gi|13879055|gb|AE006916.1AE006916 2.1E−129 Mycobacterium tuberculosis CDC1551, section 2 of 280 of the complete genome 23407 DTT03150008.1 M83822 gi|1580780|gb|M83822.1HUMCDC4REL 0 Human beige-like protein (BGL) mRNA, partial cds 23408 DTT03367008.1 NM_012090.2 gi|15011903|ref|NM_012090.2 Homo 0 sapiens actin cross-linking factor (ACF7), transcript variant 1, mRNA 23411 DTT03913023.1 AK018110 gi|12857675|dbj|AK018110.1AK018110   2E−214 Mus musculus adult male medulla oblongata cDNA, RIKEN full-length enriched library, clone: 633040 23412 DTT03978010.1 BC015529 gi|15930193|gb|BC015529.1BC015529 0 Homo sapiens, Similar to ribose 5- phosphate isomerase A, clone MGC: 9441 IMAGE: 3904718, mRNA, comp 23413 DTT04070014.1 L43411 gi|893273|gb|L43411.1HUM25DC1Z   4E−102 Homo sapiens (subclone 5_g5 from P1 H25) DNA sequence 23414 DTT04084010.1 AF259790 gi|12240019|gb|AF259790.1AF259790 2.2E−288 Desulfitobacterium sp. PCE-1 o- chlorophenol reductive dehalogenase (cprA) gene, complete cds 23415 DTT04160007.1 AF338299 gi|12958808|gb|AF338299.1AF338299 1.4E−181 Amazona ochrocephala auropalliata mitochondrial control region 1, partial sequence 23417 DTT04378009.1 AF102129 gi|5922722|gb|AF102129.1AF102129 4.7E−146 Rattus norvegicus KPL2 (Kpl2) mRNA, complete cds 23418 DTT04403013.1 AE007580 gi|15023517|gb|AE007580.1AE007580 1.5E−199 Clostridium acetobutylicum ATCC824 section 68 of 356 of the complete genome 23420 DTT04660017.1 NM_025079 gi|13376631|ref|NM_025079.1 Homo 0 sapiens hypothetical protein FLJ23231 (FLJ23231), mRNA 23421 DTT04956054.1 AF050179 gi|3319283|gb|AF050179.1AF050179 0 Homo sapiens CENP-C binding protein (DAXX) mRNA, complete cds 23422 DTT04970018.1 AK015635 gi|12854041|dbj|AK015635.1AK015635 1.4E−84 Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone: 4930486L24, full 23424 DTT05571010.1 AB014533 gi|3327079|dbj|AB014533.1AB014533 1.8E−53 Homo sapiens mRNA for KIAA0633 protein, partial cds 23426 DTT05742029.1 AF344987 gi|13448249|gb|AF344987.1AF344987 0 Hepatitis C virus isolate RDpostSC1c2 polyprotein gene, partial cds 23427 DTT06137030.1 AY049285 gi|15146287|gb|AY049285.1 Arabidopsis 2.2E−143 thaliana AT3g58570/F14P22_160 mRNA, complete cds 23428 DTT06161014.1 AJ330465 gi|15874883|emb|AJ330465.1HSA330465 2.5E−28 Homo sapiens genomic sequence surrounding NotI site, clone NR1-IM15C 23429 DTT06706019.1 AF226787 gi|12407487|gb|AF226787.1AF226787 0 Syrrhopodon confertus ribulose-1,5- bisphosphate carboxylase large subunit (rbcL) gene, partial cd 23430 DTT06837021.1 AK000658 g|7020892|dbj|AK000658.1AK000658 0 Homo sapiens cDNA FLJ20651 fis, clone KAT01814 23431 DTT07040015.1 AF047347 gi|3005557|gb|AF047347.1AF047347 0 Homo sapiens adaptor protein X11alpha mRNA, complete cds 23432 DTT07088009.1 AF326517 gi|15080738|gb|AF326517.1AF326517 0 Abies grandis pinene synthase gene, partial cds 23433 DTT07182014.1 AB035187 gi|9955412|dbj|AB035187.1AB035187 3.1E−84 Homo sapiens RHD gene, intron 1, complete sequence 23434 DTT07405044.1 AP002946 gi|16267254|dbj|AP002946.1AP002946 0 Mastacembelus favus mitochondrial DNA, complete genome 23435 DTT07408020.1 AE008061 gi|15156405|gb|AE008061.1AE008061 6.9E−245 Agrobacterium tumefaciens strain C58 circular chromosome, section 119 of 254 of the complete sequ 23438 DTT08005024.1 U18270 gi|885679|gb|U18270.1HSTMPO4 Human 5.1E−108 thymopoietin (TMPO) gene, exons 4 and 5, and complete cds for thymopoietin alpha 23439 DTT08098020.1 AF387946 gi|15021617|gb|AF387946.1AF387946 0 Homo sapiens clone J102 melanocortin 1 receptor gene, promoter region 23440 DTT08167018.1 NM_020642 gi|11034852|ref|NM_020642.1 Homo   1E−183 sapiens chromosome 11 open reading frame 17 (C11orf17), mRNA 23441 DTT08249022.1 M86752 gi|184564|gb|M86752.1HUMIEF Human 0 transformation-sensitive protein (IEF SSP 3521) mRNA, complete cds 23443 DTT08514022.1 AK001927 gi|7023494|dbj|AK001927.1AK001927 0 Homo sapiens cDNA FLJ11065 fis, clone PLACE1004868, weakly similar to MALE STERILITY PROTEIN 2 23444 DTT08527013.1 AF271388 gi|8515842|gb|AF271388.1AF271388 0 Homo sapiens CMP-N-acetylneuraminic acid synthase mRNA, complete cds 23445 DTT08595020.1 L07758 gi|177764|gb|L07758.1HUM56KDAPR 0 Human IEF SSP 9502 mRNA, complete cds 23446 DTT08711019.1 D87930 gi|2443337|dbj|D87930.1D87930 Homo 0 sapiens mRNA for myosin phosphatase target subunit 1 (MYPT1) 23447 DTT08773020.1 X15187 gi|37260|emb|X15187.1HSTRA1 Human 6.8E−298 tral mRNA for human homologue of murine tumor rejection antigen gp96 23448 DTT08874012.1 AK026442 gi|10439307|dbj|AK026442.1AK026442 0 Homo sapiens cDNA: FLJ22789 fis, clone KAIA2171 23449 DTT09387018.1 AF273672 gi|15186755|gb|AF273672.1AF273672 0 Mus musculus RANBP9 isoform 1 (Ranbp9) mRNA, complete cds 23450 DTT09396022.1 AK000913 gi|7021874|dbj|AK000913.1AK000913 0 Homo sapiens cDNA FLJ10051 fis, clone HEMBA1001281 23452 DTT09604016.1 AK022722 gi|10434285|dbj|AK022722.1AK022722 2.2E−198 Homo sapiens cDNA FLJ12660 fis, clone NT2RM4002174, moderately similar to MRP PROTEIN 23454 DTT09742009.1 AF025409 gi|2582414|gb|AF025409.1AF025409 0 Homo sapiens zinc transporter 4 (ZNT4) mRNA, complete cds 23455 DTT09753017.1 L03532 gi|187280|gb|L03532.1HUMM4PRO 5.7E−58 Human M4 protein mRNA, complete cds 23456 DTT09793019.1 AK025125 gi|10437578|dbj|AK025125.1AK025125 Homo sapiens cDNA: FLJ21472 fis, clone COL04936 23457 DTT09796028.1 AF272390 gi|8705239|gb|AF272390.1AF272390 0 Homo sapiens myosin 5c (MYO5C) mRNA, complete cds 23459 DTT10360040.1 AJ133798 gi|6453351|emb|AJ133798.1HSA133798 0 Homo sapiens mRNA for copine VI protein 23460 DTT10539016.1 AF152924 gi|5453323|gb|AF152924.1AF152924 Mus 2.6E−70 musculus syntaxin4-interacting protein synip mRNA, complete cds 23461 DTT10564022.1 AF322634 gi|12657820|gb|AF322634.1AF322634S1 0 Human herpesvirus 3 strain VZV-Iceland glycoprotein B gene, complete cds 23462 DTT10683041.1 X69392 gi|36114|emb|X69392.1HSRP26AA   3E−250 H. sapiens mRNA for ribosomal protein L26 23463 DTT10819011.1 U14568 gi|551537|gb|U14568.1HSU14568 2.6E−93 ***ALU WARNING: Human Alu-Sb subfamily consensus sequence 23465 DTT11479018.1 AF309561 gi|10954043|gb|AF309561.1AF309561 0 Homo sapiens KRAB zinc finger protein ZFQR mRNA, complete cds 23466 DTT11483012.1 U57053 gi|1616674|gb|U57053.1HSU57053 3.1E−245 Human unconventional myosin-ID (MYO1F) gene, partial cds 23467 DTT11548015.1 X05332 gi|35740|emb|X05332.1HSPSAR Human 0 mRNA for prostate specific antigen 23468 DTT11730017.1 U14572 gi|551541|gb|U14572.1HSU14572 4.7E−90 ***ALU WARNING: Human Alu-Sp subfamily consensus sequence 23471 DTT11902028.1 AK001915 gi|7023475|dbj|AK001915.1AK001915 0 Homo sapiens cDNA FLJ11053 fis, clone PLACE1004664 23472 DTT11915017.1 U66062 gi|1724068|gb|U66062.1HSU66062 5.9E−111 Human glp-1 receptor gene, promoter region and partial cds 23475 DTT12201062.1 M73791 gi|189265|gb|M73791.1HUMNOVGENE 0 Human novel gene mRNA, complete cds 23476 DTT12470020.1 AK026618 gi|10439509|dbj|AK026618.1AK026618 0 Homo sapiens cDNA: FLJ22965 fis, clone KAT10418

Example 96 Members of Protein Families

SEQ ID NOS: 22001-23477 were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein family (and thus represent members of these protein families) and/or comprising a known functional domain. Table 149 (inserted prior to claims) provides: 1) the SEQ ID NO (“SEQ ID”) of the query polynucleotide sequence; 2) the sequence name (“SEQ NAME”) used as an internal identifier of the query sequence; 3) the accession number (“PFAM ID”) of the protein family profile hit; 4) a brief description of the profile hit (“PFAM DESCRIPTION”); 5) the score (“SCORE”) of the profile hit; 6) the starting nucleotide of the profile hit (“START”); and 7) the ending nucleotide of the profile hit (“END”).

TABLE 149 SEQ ID SEQ NAME PFAM ID PFAM DESCRIPTION SCORE START END 22007 2504.C11.GZ43_365848 PF00179 Ubiquitin-conjugating 92.64 4 159 enzyme 22010 2504.E23.GZ43_365908 PF01260 AP endonuclease family 1 88.28 222 481 22046 2505.G16.GZ43_366333 PF02594 Uncharacterized ACR, 77.64 263 495 YggU family COG1872 22109 2510.N14.GZ43_369351 PF02348 Cytidylyltransferase 187.84 357 675 22126 2365.D10.GZ43_345308 PF01018 GTP1/OBG family 96.12 50 507 22134 2365.F24.GZ43_345370 PF00160 Cyclophilin type peptidyl- 120.2 251 522 prolyl cis-trans isomerase 22189 2366.L21.GZ43_345942 PF00612 IQ calmodulin-binding 33.96 415 477 motif 22189 2366.L21.GZ43_345942 PF00063 Myosin head (motor 207.12 8 369 domain) 22259 2368.O03.GZ43_346717 PF00160 Cyclophilin type peptidyl- 120.2 242 513 prolyl cis-trans isomerase 22267 2535.C23.GZ43_370158 PF02114 Phosducin 32 152 589 22334 2537.D11.GZ43_370938 PF00083 Sugar (and other) 122.88 4 288 transporter 22335 2537.D20.GZ43_370947 PF00131 Metallothionein 48.56 563 665 22349 2537.N12.GZ43_371179 PF001352 KRAB box 123.24 313 498 22363 2538.B03.GZ43_371266 PF00160 Cyclophilin type peptidyl- 117.68 320 591 prolyl cis-trans isomerase 22391 2554.A06.GZ43_375853 PF03015 Male sterility protein 44.96 605 749 22394 2554.A16.GZ43_375863 PF02348 Cytidylyltransferase 195.48 397 650 22405 2554.I10.GZ43_376049 PF03041 lef-2 31.88 479 536 22419 2565.B15.GZ43_398171 PF02271 Ubiquinol-cytochrome C 70.76 29 188 reductase complex 14 kD subunit 22422 2565.C17.GZ43_398204 PF00089 Trypsin 45.28 5 110 22482 2540.I17.GZ43_372216 PF00023 Ank repeat 75.44 444 542 22507 2541.L08.GZ43_372663 PF00499 NADH- 54.72 89 237 ubiquinone/plastoquinone oxidoreductase chain 6 22514 2506.C15.GZ43_366620 PF00076 RNA recognition motif. 44.44 70 276 (a.k.a. RRM, RBD, or RNP domain) 22521 2506.G24.GZ43_366725 PF00096 Zinc finger, C2H2 type 46.68 156 224 22527 2506.J20.GZ43_366793 PF00595 PDZ Domain (Also known 34.16 290 502 as DHR or GLGF). 22543 2542.D19.GZ43_372866 PF00098 Zinc knuckle 46.68 224 276 22563 2542.N21.GZ43_373108 PF01545 Cation efflux family 42.24 191 325 22569 2555.F16.GZ43_373295 PF02348 Cytidylyltransferase 215.04 357 713 22716 2560.H21.GZ43_375268 PF00510 Cytochrome c oxidase 37.28 224 436 subunit III 22721 2560.K10.GZ43_375329 PF01018 GTP1/OBG family 104.56 50 573 22759 2561.O17.GZ43_37658 PF00826 Ribosomal L10 79.88 46 180 22766 2456.B12.GZ43_355864 PF01545 Cation efflux family 34.16 102 236 22771 2456.D04.GZ43_355904 PF02114 Phosducin 30.52 139 576 22813 2457.J23.GZ43_356451 PF02594 Uncharacterized ACR, 77.64 189 421 YggU family COG1872 22818 2457.L21.GZ43_356497 PF00023 Ank repeat 38 208 306 22910 2464.L02.GZ43_357946 PF00076 RNA recognition motif. 34.84 244 350 a.k.a. RRM, RBD, or RNP domain) 22914 2464.N05.GZ43_357997 PF00023 Ank repeat 128.28 491 589 22935 2465.K20.GZ43_358324 PF02594 Uncharacterized ACR, 77.64 210 442 YggU family COG1872 22952 2466.I08.GZ43_360281 PF00012 Hsp70 protein 120.92 16 208 22967 2467.D10.GZ43_360547 PF00008 EGF-like domain 31.04 63 113 23002 2472.P22.GZ43_361231 PF00499 NADH- 64.72 81 209 ubiquinone/plastoquinone oxidoreductase chain 6 23011 2473.I08.GZ43_361433 PF00895 ATP synthase protein 8 66.88 5 148 23039 2475.N08.GZ43_362321 PF00804 Syntaxin 53.08 226 601 23051 2480.D13.GZ43_358588 PF03025 Papillomavirus E5 33.56 583 749 23065 2481.B06.GZ43_358917 PF00098 Zinc knuckle 35.88 79 133 23100 2483.J07.GZ43_359878 PF00142 4Fe-4S iron sulfur cluster 32.8 211 288 binding proteins, NifH/frxC family 23101 2483.K02.GZ43_359897 PF00160 Cyclophilin type peptidyl- 117.52 244 516 prolyl cis-trans isomerase 23107 2488.B07.GZ43_362475 PF01260 AP endonuclease family 1 79.88 251 614 23128 2489.F09.GZ43_362957 PF02348 Cytidylyltransferase 174.36 347 591 23183 2496.I06.GZ43_364281 PF02790 Cytochrome C oxidase 45.8 131 242 subunit II, transmembrane domain 23207 2562.B09.GZ43_375496 PF00826 Ribosomal L10 106.28 49 341 23216 2562.E14.GZ43_375573 PF00023 Ank repeat 87.04 230 328 23225 2562.H18.GZ43_375649 PF02594 Uncharacterized ACR, 65.44 206 437 YggU family COG1872 23244 2507.C03.GZ43_366992 PF00083 Sugar (and other) 95.52 107 355 transporter 23267 2499.I09.GZ43_365436 PF00160 Cyclophilin type peptidyl- 43.24 139 238 prolyl cis-trans isomerase

In addition, SEQ ID NOS:23478-23568 were also used to conduct a profile search as described above. Several of the polypeptides of the invention were found to have characteristics of a polypeptide belonging to a known protein family (and thus represent members of these protein families) and/or comprising a known functional domain. Table 150 (inserted prior to claims) provides: 1) the SEQ ID NO (“SEQ ID”) of the query protein sequence; 2) the sequence name (“PROTEIN SEQ NAME”) used as an internal identifier of the query sequence; 3) the accession number (“PFAM ID”) of the protein family profile hit; 4) a brief description of the profile hit (“PFAM DESCRIPTION”); 5) the score (“SCORE”) of the profile hit; 6) the starting residue of the profile hit (“START”); and 7) the ending residue of the profile hit (“END”).

Some SEQ ID NOS exhibited multiple profile hits where the query sequence contains overlapping profile regions, and/or where the sequence contains two different functional domains. Each of the profile hits of Tables 8 and 9 is described in more detail below. The acronyms for the profiles (provided in parentheses) are those used to identify the profile in the Pfam, Prosite, and InterPro databases. The Pfam database can be accessed through web sites supported by Genome Sequencing Center at the Washington University School of Medicine or by the European Molecular Biology Laboratories in Heidelberg, Germany. The Prosite database can be accessed at the ExPASy Molecular Biology Server on the internet. The InterPro database can be accessed at a web site supported by the EMBL European Bioinformatics Institute. The public information available on the Pfam, Prosite, and InterPro databases regarding the various profiles, including but not limited to the activities, function, and consensus sequences of various proteins families and protein domains, is incorporated herein by reference.

TABLE 150 PROTEIN SEQ SEQ ID NAME PFAM ID PFAM DESCRIPTION SCORE START END 23481 DTP00514038.1 PF00587 tRNA synthetase class II core 33.42 1 116 domain (G, H, P, S and T) 23482 DTP00740019.1 PF00012 Hsp70 protein 948.22 27 564 23484 DTP01169031.1 PF00023 Ank repeat 159.66 82 114 23484 DTP01169031.1 PF00023 Ank repeat 159.66 181 213 23484 DTP01169031.1 PF00023 Ank repeat 159.66 148 180 23484 DTP01169031.1 PF00023 Ank repeat 159.66 115 147 23484 DTP01169031.1 PF00023 Ank repeat 159.66 82 114 23484 DTP01169031.1 PF00023 Ank repeat 159.66 49 81 23484 DTP01169031.1 PF00023 Ank repeat 159.66 16 48 23484 DTP01169031.1 PF00023 Ank repeat 159.66 181 213 23484 DTP01169031.1 PF00023 Ank repeat 159.66 115 147 23484 DTP01169031.1 PF00023 Ank repeat 159.66 49 81 23484 DTP01169031.1 PF00023 Ank repeat 159.66 16 48 23484 DTP01169031.1 PF00023 Ank repeat 159.66 148 180 23486 DTP01315019.1 PF01839 FG-GAP repeat 255.09 427 479 23486 DTP01315019.1 PF01839 FG-GAP repeat 255.09 49 111 23486 DTP01315019.1 PF01839 FG-GAP repeat 255.09 248 300 23486 DTP01315019.1 PF01839 FG-GAP repeat 255.09 303 362 23486 DTP01315019.1 PF01839 FG-GAP repeat 255.09 365 424 23495 DTP02737026.1 PF01423 Sm protein 31.6 19 66 23496 DTP02850014.1 PF00804 Syntaxin 156.59 1 292 23496 DTP02850014.1 PF00804 Syntaxin 156.59 1 292 23496 DTP02850014.1 PF00804 Syntaxin 156.59 1 292 23510 DTP04403022.1 PF00400 WD domain, G-beta repeat 35.93 80 116 23510 DTP04403022.1 PF00400 WD domain, G-beta repeat 35.93 38 74 23510 DTP04403022.1 PF00400 WD domain, G-beta repeat 35.93 1 33 23512 DTP04660026.1 PF00083 Sugar (and other) transporter 234.43 1 484 23512 DTP04660026.1 PF00083 Sugar (and other) transporter 234.43 1 484 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76 105 208 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76 7 97 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76 105 208 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76 7 97 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76 105 208 23518 DTP05742038.1 PF01018 GTP1/OBG family 133.76 7 97 23519 DTP06137039.1 PF02271 Ubiquinol-cytochrome C 141.38 4 154 reductase complex 14 kD subunit 23521 DTP06706028.1 PF00054 Laminin G domain 63.34 56 178 23521 DTP06706028.1 PF00054 Laminin G domain 63.34 281 292 23523 DTP07040024.1 PF00640 Phosphotyrosine interaction 233.89 461 618 domain (PTB/PID). 23523 DTP07040024.1 PF00595 PDZ domain (Also known as 85.47 656 742 DHR or GLGF). 23532 DTP08249031.1 PF00515 TPR Domain 115 4 37 23532 DTP08249031.1 PF00515 TPR Domain 115 72 105 23532 DTP08249031.1 PF00515 TPR Domain 115 38 71 23532 DTP08249031.1 PF00515 TPR Domain 115 259 292 23532 DTP08249031.1 PF00515 TPR Domain 115 300 333 23532 DTP08249031.1 PF00515 TPR Domain 115 225 258 23535 DTP08527022.1 PF02348 Cytidylyltransferase 48.59 1 166 23535 DTP08527022.1 PF02348 Cytidylyltransferase 48.59 1 166 23535 DTP08527022.1 PF02348 Cytidylyltransferase 48.59 1 166 23535 DTP08527022.1 PF02348 Cytidylyltransferase 48.59 1 166 23536 DTP08595029.1 PF00400 WD domain, G-beta repeat 80.04 183 221 23536 DTP08595029.1 PF00400 WD domain, G-beta repeat 80.04 236 273 23536 DTP08595029.1 PF00400 WD domain, G-beta repeat 80.04 365 402 23536 DTP08595029.1 PF00400 WD domain, G-beta repeat 80.04 279 316 23536 DTP08595029.1 PF00400 WD domain, G-beta repeat 80.04 325 357 23537 DTP08711028.1 PF00023 Ank repeat 81.96 22 54 23537 DTP08711028.1 PF00023 Ank repeat 81.96 55 87 23538 DTP08773029.1 PF00183 Hsp90 protein 100.71 104 173 23540 DTP09387027.1 PF00069 Protein kinase domain 224.56 76 342 23545 DTP09742018.1 PF01545 Cation efflux family 368.71 114 418 23545 DTP09742018.1 PF01545 Cation efflux family 368.71 114 418 23548 DTP09796037.1 PF00612 IQ calmodulin-binding motif 87.63 879 899 23548 DTP09796037.1 PF00612 IQ calmodulin-binding motif 87.63 856 876 23548 DTP09796037.1 PF00612 IQ calmodulin-binding motif 87.63 831 851 23548 DTP09796037.1 PF00612 IQ calmodulin-binding motif 87.63 808 828 23548 DTP09796037.1 PF00612 IQ calmodulin-binding motif 87.63 780 800 23548 DTP09796037.1 PF00612 IQ calmodulin-binding motif 87.63 757 777 23548 DTP09796037.1 PF01843 DIL domain 125.23 1574 1679 23548 DTP09796037.1 PF00063 Myosin head (motor domain) 1228.24 69 741 23550 DTP10360049.1 PF00168 C2 domain 50.07 26 114 23550 DTP10360049.1 PF00168 C2 domain 50.07 228 315 23551 DTP10539025.1 PF00595 PDZ domain (Also known as 32.34 5 84 DHR or GLGF). 23553 DTP10683050.1 PF00467 KOW motif 89.22 49 107 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 402 424 23556 DTP11479027.1 PF01352 KRAB box 134.58 8 70 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 374 396 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 346 368 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 318 340 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 290 312 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 262 284 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 234 256 23556 DTP11479027.1 PF00096 Zinc finger, C2H2 type 209.31 206 228 23557 DTP11483021.1 PF00063 Myosin head (motor domain) 339.24 117 271 23557 DTP11483021.1 PF00063 Myosin head (motor domain) 339.24 34 115 23558 DTP11548024.1 PF00089 Trypsin 272.53 25 253 23564 DTP11966049.1 PF00023 Ank repeat 165.68 49 81 23564 DTP11966049.1 PF00023 Ank repeat 165.68 148 180 23564 DTP11966049.1 PF00023 Ank repeat 165.68 181 214 23564 DTP11966049.1 PF00023 Ank repeat 165.68 148 180 23564 DTP11966049.1 PF00023 Ank repeat 165.68 115 147 23564 DTP11966049.1 PF00023 Ank repeat 165.68 82 114 23564 DTP11966049.1 PF00023 Ank repeat 165.68 49 81 23564 DTP11966049.1 PF00023 Ank repeat 165.68 181 214 23564 DTP11966049.1 PF00023 Ank repeat 165.68 181 214 23564 DTP11966049.1 PF00023 Ank repeat 165.68 16 48 23564 DTP11966049.1 PF00023 Ank repeat 165.68 115 147 23564 DTP11966049.1 PF00023 Ank repeat 165.68 82 114 23564 DTP11966049.1 PF00023 Ank repeat 165.68 16 48 23564 DTP11966049.1 PF00023 Ank repeat 165.68 148 180 23564 DTP11966049.1 PF00023 Ank repeat 165.68 115 147 23564 DTP11966049.1 PF00023 Ank repeat 165.68 82 114 23564 DTP11966049.1 PF00023 Ank repeat 165.68 49 81 23564 DTP11966049.1 PF00023 Ank repeat 165.68 16 48 23566 DTP12201071.1 PF00826 Ribosomal L10 467.36 1 176 23566 DTP12201071.1 PF00826 Ribosomal L10 467.36 1 176

Example 97 Detection of Differential Expression Using Arrays and Source of Patient Tissue Samples

mRNA isolated from samples of cancerous and normal breast, colon, and prostate tissue obtained from patients were analyzed to identify genes differentially expressed in cancerous and normal cells. Normal and cancerous tissues were collected from patients using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001).

Table 151 (inserted prior to claims) provides information about each patient from which colon tissue samples were isolated, including: the Patient ID (“PT ID”) and Path ReportID (“Path ID”), which are numbers assigned to the patient and the pathology reports for identification purposes; the group (“Grp”) to which the patients have been assigned; the anatomical location of the tumor (“Anatom Loc”); the primary tumor size (“Size”); the primary tumor grade (“Grade”); the identification of the histopathological grade (“Histo Grade”); a description of local sites to which the tumor had invaded (“Local Invasion”); the presence of lymph node metastases (“Lymph Met”); the incidence of lymph node metastases (provided as a number of lymph nodes positive for metastasis over the number of lymph nodes examined) (“Lymph Met Incid”); the regional lymphnode grade (“Reg Lymph Grade”); the identification or detection of metastases to sites distant to the tumor and their location (“Dist Met & Loc”); the grade of distant metastasis (“Dist Met Grade”); and general comments about the patient or the tumor (“Comments”). Histophatology of all primary tumors indicated the tumor was adenocarcinmoa except for Patient ID Nos. 130 (for which no information was provided), 392 (in which greater than 50% of the cells were mucinous carcinoma), and 784 (adenosquamous carcinoma). Extranodal extensions were described in three patients, Patient ID Nos. 784, 789, and 791. Lymphovascular invasion was described in Patient ID Nos. 128, 278, 517, 534, 784, 786, 789, 791, 890, and 892. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791.

Table 152 below provides information about each patient from which the prostate tissue samples were isolated, including: 1) the “Patient ID”, which is a number assigned to the patient for identification purposes; 2) the “Tissue Type”; and 3) the “Gleason Grade” of the tumor. Histopathology of all primary tumors indicated the tumor was adenocarcinoma.

TABLE 152 Prostate patient data. Gleason Patient ID Tissue Type Grade 93 Prostate Cancer 3 + 4 94 Prostate Cancer 3 + 3 95 Prostate Cancer 3 + 3 96 Prostate Cancer 3 + 3 97 Prostate Cancer 3 + 2 100 Prostate Cancer 3 + 3 101 Prostate Cancer 3 + 3 104 Prostate Cancer 3 + 3 105 Prostate Cancer 3 + 4 106 Prostate Cancer 3 + 3 138 Prostate Cancer 3 + 3 151 Prostate Cancer 3 + 3 153 Prostate Cancer 3 + 3 155 Prostate Cancer 4 + 3 171 Prostate Cancer 3 + 4 173 Prostate Cancer 3 + 4 231 Prostate Cancer 3 + 4 232 Prostate Cancer 3 + 3 251 Prostate Cancer 3 + 4 282 Prostate Cancer 4 + 3 286 Prostate Cancer 3 + 3 294 Prostate Cancer 3 + 4 351 Prostate Cancer 5 + 4 361 Prostate Cancer 3 + 3 362 Prostate Cancer 3 + 3 365 Prostate Cancer 3 + 2 368 Prostate Cancer 3 + 3 379 Prostate Cancer 3 + 4 388 Prostate Cancer 5 + 3 391 Prostate Cancer 3 + 3 420 Prostate Cancer 3 + 3 425 Prostate Cancer 3 + 3 428 Prostate Cancer 4 + 3 431 Prostate Cancer 3 + 4 492 Prostate Cancer 3 + 3 493 Prostate Cancer 3 + 4 496 Prostate Cancer 3 + 3 510 Prostate Cancer 3 + 3 511 Prostate Cancer 4 + 3 514 Prostate Cancer 3 + 3 549 Prostate Cancer 3 + 3 552 Prostate Cancer 3 + 3 858 Prostate Cancer 3 + 4 859 Prostate Cancer 3 + 4 864 Prostate Cancer 3 + 4 883 Prostate Cancer 4 + 4 895 Prostate Cancer 3 + 3 901 Prostate Cancer 3 + 3 909 Prostate Cancer 3 + 3 921 Prostate Cancer 3 + 3 923 Prostate Cancer 4 + 3 934 Prostate Cancer 3 + 3 1134 Prostate Cancer 3 + 4 1135 Prostate Cancer 3 + 3 1136 Prostate Cancer 3 + 4 1137 Prostate Cancer 3 + 3 1138 Prostate Cancer 4 + 3

Table 153 provides information about each patient from which the breast tissue samples were isolated, including: 1) the “Pat Num”, a number assigned to the patient for identification purposes; 2) the “Histology”, which indicates whether the tumor was characterized as an intraductal carcinoma (IDC) or ductal carcinoma in situ (DCIS); 3) the incidence of lymph node metastases (LMF), represented as the number of lymph nodes positive to metastases out of the total number examined in the patient; 4) the “Tumor Size”; 5) “TNM Stage”, which provides the tumor grade (T#), where the number indicates the grade and “p” indicates that the tumor grade is a pathological classification; regional lymph node metastasis (N#), where “0” indicates no lymph node metastases were found, “1” indicates lymph node metastases were found, and “X” means information not available and; the identification or detection of metastases to sites distant to the tumor and their location (M#), with “X” indicating that no distant mesatses were reported; and the stage of the tumor (“Stage Grouping”). “nr” indicates “no reported”.

TABLE 153 Breast cancer patient data Pat Tumor Stage Num Histology LMF Size TNM Stage Grouping 280 IDC, DCIS + D2 nr 2 cm T2NXMX probable Stage II 284 IDC, DCIS 0/16 2 cm T2pN0MX Stage II 285 IDC, DCIS nr 4.5 cm T2NXMX probable Stage II 291 IDC, DCIS 0/24 4.5 cm T2pN0MX Stage II 302 IDC, DCIS nr 2.2 cm T2NXMX probable Stage II 375 IDC, DCIS nr 1.5 cm T1NXMX probable Stage I 408 IDC 0/23 3.0 cm T2pN0MX Stage II 416 IDC 0/6 3.3 cm T2pN0MX Stage II 421 IDC, DCIS nr 3.5 cm T2NXMX probable Stage II 459 IDC 2/5 4.9 cm T2pN1MX Stage II 465 IDC 0/10 6.5 cm T3pN0MX Stage II 470 IDC, DCIS 0/6 2.5 cm T2pN0MX Stage II 472 IDC, DCIS 6/45 5.0+ cm T3pN1MX Stage III 474 IDC 0/18 6.0 cm T3pN0MX Stage II 476 IDC 0/16 3.4 cm T2pN0MX Stage II 605 IDC, DCIS 1/25 5.0 cm T2pN1MX Stage II 649 IDC, DCIS 1/29 4.5 cm T2pN1MX Stage II

Identification of Differentially Expressed Genes

cDNA probes were prepared from total RNA isolated from the patient cells described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogeneous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample.

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Table 154 (inserted prior to claims) provides the results for gene products expressed by at least 2-fold or greater in cancerous prostate, colon, or breast tissue samples relative to normal tissue samples in at least 20% of the patients tested. Table 154 includes: 1) the SEQ ID NO (“SEQ ID”) assigned to each sequence for use in the present specification; 2) the Cluster Identification No. (“CLUSTER”); 3) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 2-fold greater in cancerous breast tissue than in matched normal tissue (“BREAST PATIENTS>=2×”); 4) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was less than or equal to ½ of the expression level in matched normal breast cells (“BREAST PATIENTS<=half×”); 5) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 2-fold greater in cancerous colon tissue than in matched normal tissue (“COLON PATIENTS>=2×”); 6) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was less than or equal to ½ of the expression level in matched normal colon cells (“COLON PATIENTS<=half×”); 7) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 2-fold greater in cancerous prostate tissue than in matched normal tissue (“PROSTATE PATIENTS>=2×”); and 8) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was less than or equal to ½ of the expression level in matched normal prostate cells (“PROSTATE PATIENTS<=half×”).

These data provide evidence that the genes represented by the polynucleotides having the indicated sequences are differentially expressed in breast cancer as compared to normal non-cancerous breast tissue, are differentially expressed in colon cancer as compared to normal non-cancerous colon tissue, and are differentially expressed in prostate cancer as compared to normal non-cancerous prostate tissue.

TABLE 154 BREAST BREAST COLON COLON PROSTATE PROSTATE PATIENTS >= PATIENTS <= PATIENTS >= PATIENTS <= PATIENTS >= PATIENTS <= SEQ ID CLONE ID 2x halfx 2x halfx 2x halfx 22004 M00072944A:C07 35 22008 M00072947B:G04 32.5 22009 M00072947D:G05 27.5 22015 M00072963B:G11 40 22016 M00072967A:G07 25 22018 M00072968A:F08 22.5 22020 M00072968D:E05 32.5 22021 M00072970C:B07 25 22024 M00072971C:B07 22.5 22028 M00072975A:D11 23.5 22034 M00073001A:F07 27.5 22038 M00073003A:E06 42.5 22039 M00073003B:E10 27.5 22042 M00073006A:H08 23.5 22043 M00073006C:D07 27.5 22045 M00073009B:C08 32.5 52.4 22048 M00073013A:D10 32.5 22049 M00073013A:F10 20 22050 M00073013C:B10 32.5 22052 M00073014D:F01 40 22054 M00073015A:H06 47.5 22061 M00073020C:F07 32.5 22062 M00073020D:C06 37.5 22063 M00073021C:E04 30 22071 M00073030B:C02 22.5 22072 M00073030C:A02 20 22073 M00073036C:H10 25 22086 M00073043D:H09 32.5 22090 M00073044C:G12 32.5 22094 M00073045C:E06 22.5 22096 M00073045D:B04 30 22105 M00073048C:B01 20 22107 M00073049A:H04 27.5 49.2 22108 M00073049B:B03 23.5 40 31.7 22109 M00073049B:B06 20 22110 M00073049C:C09 20 22136 M00073066C:D02 27.5 22142 M00073070B:B06 32.5 22146 M00073074D:A04 20 22153 M00073086D:B05 30 22156 M00073091B:C04 20 22163 M00073424D:C03 52.9 22171 M00073403C:C10 30 22173 M00073403C:E11 29.4 52.5 22176 M00073412C:E07 30 22177 M00073435C:E06 27.5 22178 M00073412D:B07 35.3 42.5 22189 M00073430C:B02 32.5 22196 M00073442A:F07 25 22197 M00073442B:D12 27.5 20.6 22199 M00073446C:A03 22.5 22201 M00073447D:F01 45 38.1 22204 M00073453C:C09 41.2 22212 M00073469B:A09 27.5 36.5 22216 M00073474C:F08 30 22.2 22220 M00073484B:A05 23.5 30 22.2 22228 M00073497C:D03 29.4 30 22233 M00073513A:G07 23.5 25.4 22236 M00073517A:A06 32.5 22241 M00073529A:F03 20 22242 M00073530B:A02 20 54.0 22243 M00073531B:H02 50.8 22246 M00073539C:H05 27.5 22247 M00073541B:C10 30 22248 M00073547B:F04 22.5 22249 M00073547C:D02 35 22256 M00073554B:D11 37.5 22264 M00073568A:G06 32.5 22265 M00073568C:G07 25 22269 M00073576B:E03 22.5 22270 M00073576C:C11 20 22273 M00073580A:D08 32.5 22280 M00073598D:E11 40 22284 M00073601D:D08 32.5 22286 M00073603B:C03 30 22288 M00073603C:C02 76.5 67.5 22290 M00073604B:B07 30 22294 M00073605B:F11 58.8 22299 M00073614C:F06 60 22300 M00073615D:E03 82.5 22301 M00073616A:F06 32.5 28.6 22304 M00073621D:A04 27.5 22316 M00073633D:A04 23.5 52.5 22318 M00073634C:H08 23.5 85 39.7 22319 M00073635D:C10 35.3 22323 M00073638A:A12 47.5 22325 M00073639A:G08 27.5 22340 M00073651C:F06 29.4 27.5 36.5 22342 M00073652D:B11 64.7 70 22343 M00073655B:A04 37.5 22353 M00073669A:F04 20 22354 M00073669B:E12 23.5 27.5 22357 M00073687A:D11 50 22.2 22361 M00073672D:E09 35 42.9 22367 M00073677B:F01 32.5 22369 M00073678B:H02 35 22372 M00073681A:F12 29.4 25.4 22377 M00073689C:C09 41.3 22382 M00073696C:D11 35.3 22384 M00073697C:F11 29.4 34.9 22388 M00073700B:D12 30 22390 M00073708D:E10 23.8 22392 M00073709B:F01 25 22394 M00073709C:A02 22.5 22398 M00073713D:E07 27.5 22399 M00073715A:F05 20 31.7 22400 M00073715B:B06 37.5 27.0 22401 M00073717C:A12 37.5 22403 M00073720D:H11 27.5 20.6 22408 M00073735C:E04 23.8 22413 M00073743C:F03 25 22417 M00073748B:F07 35 22424 M00073754B:D05 37.5 22436 M00073765A:E02 32.5 22439 M00073766B:B07 22.5 22442 M00073772B:E07 22.2 22450 M00073779B:B11 32.5 22462 M00073798A:H03 35 22464 M00073801B:A10 35 22467 M00073809C:E09 23.5 45 25.4 22469 M00073813D:B06 27.0 22470 M00073814C:B04 71.4 22473 M00073790A:A12 36.5 22480 M00073799A:G02 37.5 22481 M00073799D:G04 30 22486 M00073813A:E06 32.5 22487 M00073813B:A01 30 22493 M00073822C:E02 35 22494 M00073824A:C04 38.1 22497 M00073832A:A06 20 20.6 22500 M00073834A:H10 35 22502 M00073834D:H06 25 31.7 22503 M00073836D:E05 23.8 22506 M00073838B:F09 25 22509 M00073839A:D05 23.5 47.5 41.3 22513 M00073850A:H09 54.0 22532 M00073867D:F10 36.5 22533 M00073871B:C12 32.5 22534 M00073872C:B09 22.5 22535 M00073872D:B01 32.5 22536 M00073872D:E10 22.5 22544 M00073883B:D03 22.5 22550 M00073892B:F12 32.5 22555 M00073905B:A03 55.6 22562 M00073897B:B11 30 22564 M00073899A:D06 32.5 22565 M00073911B:G10 23.8 22567 M00073916A:B07 42.5 23.8 22572 M00073923C:A04 29.4 22.5 22575 M00073931D:E02 27.5 22577 M00073936D:E05 25 22579 M00073908C:D09 40 27.0 22599 M00073944D:A07 27.5 22620 M00073968B:B06 27.5 57.1 22625 M00073979C:G07 37.5 44.4 22634 M00073988D:F09 38.1 22641 M00073979B:B05 27.5 66.7 22645 M00073988C:G08 40 22654 M00074011D:C05 42.5 22656 M00074013C:C09 20 22659 M00074015A:C03 22.5 22665 M00074020D:G10 40 22669 M00074025A:F06 25 36.5 22670 M00074025B:A12 20.6 22671 M00074026C:H09 32.5 22687 M00074053C:E05 25.0 30 22695 M00074059B:G10 27.5 22703 M00074075B:A09 27.5 22706 M00074079A:E07 42.5 31.7 22708 M00074084D:B04 33.3 22710 M00074085B:E06 23.8 22712 M00074087B:C09 28.6 22713 M00074087C:G05 23.8 22717 M00074089D:E03 20 54.0 22720 M00074093B:A03 23.5 27.5 22722 M00074094B:F10 52.4 22723 M00074096D:G12 25.4 22726 M00074098C:B09 23.8 22727 M00074099C:B09 20 22729 M00074101D:D07 35 22730 M00074102A:C04 37.5 22733 M00074107C:C08 35 22741 M00074131A:H09 37.5 27.0 22742 M00074132C:F10 32.5 22.2 22747 M00074138D:A08 45 22.2 22749 M00074142B:C11 32.5 22750 M00074142D:A10 22.5 22753 M00074122A:B02 37.5 22756 M00074132A:E11 22.5 22757 M00074132B:B07 35 20.6 22758 M00074134A:G11 27.5 22759 M00074149A:B10 41.2 47.5 22762 M00074153D:A05 37.5 22765 M00074157C:G08 25 22767 M00074158C:F12 37.5 22769 M00074159C:A05 25 22777 M00074174A:C02 27.5 27.0 22782 M00074177B:H08 35 22785 M00074179C:B01 27.5 28.6 22787 M00074184D:B01 37.5 28.6 22789 M00074191C:D08 57.1 22790 M00074192C:C10 33.3 22793 M00074198C:A12 29.4 45 31.7 22794 M00074198D:D10 36.5 22800 M00074203D:F01 40 22802 M00074206A:H12 40 22.2 22806 M00074208B:F09 22.5 41.3 22811 M00074215A:F09 42.5 22813 M00074216D:H03 35 22819 M00074223B:D12 30 22821 M00074225A:H12 25 22827 M00074234A:C05 30 22830 M00074234D:F12 37.5 22834 M00074242D:F09 25 22837 M00074247B:G11 27.5 22839 M00074248C:E12 25.4 22840 M00074249C:B11 27.5 22846 M00074251C:E03 35 22849 M00074253C:F03 32.5 22850 M00074255B:A01 20 22851 M00074258A:H12 32.5 22861 M00074271B:E11 25 22869 M00074280D:H03 20 31.7 22870 M00074284B:B03 27.5 25.4 22873 M00074288A:F11 45 20.6 22874 M00074290A:G10 37.5 22875 M00074290C:B05 20.6 22877 M00074293D:B05 20 22878 M00074293D:H07 32.5 22882 M00074304B:C09 22.5 39.7 22883 M00074304D:D07 36.5 22884 M00074306A:B09 27.5 22886 M00074310D:D02 35 25.4 22888 M00074315B:A03 22.5 22892 M00074835A:H10 40 22893 M00074835B:F12 22.5 22895 M00074837A:E01 35 22899 M00074843D:D02 25 65.1 22900 M00074844B:B02 58.8 20 22901 M00074844D:F09 30 20.6 22905 M00074847B:G03 30 22909 M00074852B:A02 37.5 22912 M00074854A:C11 40 22913 M00074855B:A05 27.5 22917 M00074863D:F07 27.5 22919 M00074317D:B08 20.6 22920 M00074320C:A06 54.0 22921 M00074865A:F05 20 50.8 22923 M00074871C:G05 20 22926 M00074879A:A02 35 22.2 22930 M00074890A:E03 20 20.6 22931 M00074895D:H12 20.6 22934 M00074901C:E05 27.5 22938 M00074905D:A01 35 30.2 22941 M00074912B:A10 65.1 22943 M00074916A:H03 30 22949 M00074927D:G09 22.5 22954 M00074936B:E10 37.5 22955 M00074939B:A06 32.5 22959 M00074966D:E08 34.9 22962 M00074974C:E11 22.2 22964 M00074954A:H06 20 22975 M00072985A:C12 20 22981 M00072996B:A10 27.5 20.6 22984 M00072997D:H06 40 20.6 22986 M00074333D:A11 41.2 47.5 22990 M00074343C:A03 30 22998 M00074366A:H07 27.5 42.9 23004 M00074392C:D02 32.5 23006 M00074417D:F07 23.5 67.5 23008 M00074406B:F10 27.5 23012 M00074391B:D02 27.5 23019 M00074461D:E04 47.5 25.4 23025 M00074488C:C08 32.5 23027 M00074501A:G07 49.2 23029 M00074515A:E02 25.4 23030 M00074515C:A11 32.5 23031 M00074516B:H03 23.8 23032 M00074525A:B05 20.6 23039 M00074561D:D12 30 28.6 23040 M00074566B:A04 35 23044 M00074555A:E10 27.5 23045 M00074561A:B09 40 23052 M00074582D:B09 25.4 23057 M00074596D:B12 20 22.2 23058 M00074606C:G02 29.4 23064 M00074628C:D03 37.5 23067 M00074637A:C02 20 23068 M00074638D:C12 29.4 35 23069 M00074639A:C08 30 23073 M00074662B:A05 35.3 23078 M00074676D:H07 22.5 23080 M00074681D:A02 32.5 23082 M00074699B:C03 32.5 23083 M00074701D:H09 25 23086 M00074713B:F02 20 39.7 23089 M00074723D:D05 27.5 23092 M00074740B:F06 27.5 23095 M00074752A:D08 32.5 20.6 23099 M00074765D:F06 40 23102 M00074773C:G03 20 23103 M00074774A:D03 31.7 23105 M00074780C:C02 20 23110 M00075000A:D06 32.5 23117 M00074800B:H01 35 23120 M00074825C:E06 30 23122 M00075018A:G04 30 23134 M00075035C:C09 32.5 23135 M00075045D:H03 25 23145 M00075153C:C11 22.5 23146 M00075161A:E05 30 23152 M00075152D:C06 30 23155 M00075160A:E04 42.5 23163 M00075174D:D06 27.5 23167 M00075199D:D11 29.4 36.5 23168 M00075201D:A05 30 23169 M00075203A:G06 35 20.6 23179 M00075245A:A06 41.2 37.5 28.6 23189 M00075283A:F04 34.9 23198 M00075329B:E10 25.0 62.5 23203 M00075344D:A08 22.5 23224 M00075379A:E07 27.5 23225 M00075383A:B11 25 23227 M00075409A:E04 25 23235 M00075448B:G11 35 20.6 23239 M00075460C:B06 35.3 62.5 20.6 23245 M00075504B:A10 32.5 23250 M00075514A:G12 32.5 23266 M00075621A:F06 20 20.6 23386 23.5 23387 34.3 23388 23.5 67.5 23390 35.3 26.1 23400 32.5 23402 41.3 23403 23404 30.0 28.6 23426 36.6 23427 42.9 38.2 23429 31.6 23434 55.0 23438 21.3 21.5 23439 30.0 23444 23445 27.5 23447 29.4 32.6 23449 35.3 60.9 23461 29.4 23462 41.2 36.2 23463 27.5 23472 23.4 23474 37.5 23475 35.3 54.3

Example 98 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells can be further analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

Methods for analysis using antisense technology are well known in the art. For example, a number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein can be designed as antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of antisense oligomers specific to each candidate target are designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors considered when designing antisense oligonucleotides include: 1) the expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells can be analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

A number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein can be designed as potential antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of anti sense oligomers specific to each candidate target are designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors that are considered when designing antisense oligonucleotides include: 1) the secondary structure of oligonucleotides; 2) the secondary structure of the target gene; 3) the specificity with no or minimum cross-hybridization to other expressed genes; 4) stability; 5) length and 6) terminal GC content. The antisense oligonucleotide is designed so that it will hybridize to its target sequence under conditions of high stringency at physiological temperatures (e.g., an optimal temperature for the cells in culture to provide for hybridization in the cell, e.g., about 37° C.), but with minimal formation of homodimers.

Using the sets of oligomers and the HYBsimulator program, three to ten antisense oligonucleotides and their reverse controls are designed and synthesized for each candidate mRNA transcript, which transcript is obtained from the gene corresponding to the target polynucleotide sequence of interest. Once synthesized and quantitated, the oligomers are screened for efficiency of a transcript knock-out in a panel of cancer cell lines. The efficiency of the knock-out is determined by analyzing mRNA levels using lightcycler quantification. The oligomers that resulted in the highest level of transcript knock-out, wherein the level was at least about 50%, preferably about 80-90%, up to 95% or more up to undetectable message, are selected for use in a cell-based proliferation assay, an anchorage independent growth assay, and an apoptosis assay.

The ability of each designed antisense oligonucleotide to inhibit gene expression is tested through transfection into LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate carcinoma cells. For each transfection mixture, a carrier molecule (such as a lipid, lipid derivative, lipid-like molecule, cholesterol, cholesterol derivative, or cholesterol-like molecule) is prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide is then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide is further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, the carrier molecule, typically in the amount of about 1.5-2 nmol carrier/μg antisense oligonucleotide, is diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide is immediately added to the diluted carrier and mixed by pipetting up and down. Oligonucleotide is added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interest in the transfected cells is quantitated in the cancer cell lines using the Roche LightCycler™ real-time PCR machine. Values for the target mRNA are normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water is added to a total volume of 12.5 μl. To each tube is added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents are mixed by pipetting up and down, and the reaction mixture is incubated at 42° C. for 1 hour. The contents of each tube are centrifuged prior to amplification.

An amplification mixture is prepared by mixing in the following order: 1×PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT is added, and amplification is carried out according to standard protocols. The results are expressed as the percent decrease in expression of the corresponding gene product relative to non-transfected cells, vehicle-only transfected (mock-transfected) cells, or cells transfected with reverse control oligonucleotides.

Example 99 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferation can be assessed in metastatic breast cancer cell lines (MDA-MB-231 (“231”)); SW620 colon colorectal carcinoma cells; SKOV3 cells (a human ovarian carcinoma cell line); or LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells.

Cells are plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide is diluted to 2 μM in OptiMEM™. The oligonucleotide-OptiMEM™ can then be added to a delivery vehicle, which delivery vehicle can be selected so as to be optimized for the particular cell type to be used in the assay. The oligo/delivery vehicle mixture is then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments can be about 300 nM.

Antisense oligonucleotides are prepared as described above. Cells are transfected overnight at 37° C. and the transfection mixture is replaced with fresh medium the next morning. Transfection is carried out as described above 8.

Those antisense oligonucleotides that result in inhibition of proliferation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit proliferation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of proliferation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit proliferation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 100 Effect of Gene Expression on Cell Migration

The effect of gene expression on the inhibition of cell migration can be assessed in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells using static endothelial cell binding assays, non-static endothelial cell binding assays, and transmigration assays.

For the static endothelial cell binding assay, antisense oligonucleotides are prepared as described above. Two days prior to use, prostate cancer cells (CaP) are plated and transfected with antisense oligonucleotide as described above On the day before use, the medium is replaced with fresh medium, and on the day of use, the medium is replaced with fresh medium containing 2 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in DMEM/1% BSA/10 mM HEPES pH 7.0. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

Endothelial cells (EC) are plated onto 96-well plates at 40-50% confluence 3 days prior to use. On the day of use, EC are washed 1× with PBS and 50λ DMDM/1% BSA/10 mM HEPES pH 7 is added to each well. To each well is then added 50K (50λ) CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. The plates are incubated for an additional 30 min and washed 5× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 100 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the non-static endothelial cell binding assay, CaP are prepared as described above. EC are plated onto 24-well plates at 30-40% confluence 3 days prior to use. On the day of use, a subset of EC are treated with cytokine for 6 hours then washed 2× with PBS. To each well is then added 150-200K CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. Plates are placed on a rotating shaker (70 RPM) for 30 min and then washed 3× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 500 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the transmigration assay, CaP are prepared as described above with the following changes. On the day of use, CaP medium is replaced with fresh medium containing 5 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in EGM-2-MV medium. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

EC are plated onto FluorBlok transwells (BD Biosciences) at 30-40% confluence 5-7 days before use. Medium is replaced with fresh medium 3 days before use and on the day of use. To each transwell is then added 50K labeled CaP. 30 min prior to the first fluorescence reading, 10 μg of FITC-dextran (10K MW) is added to the EC plated filter. Fluorescence is then read at multiple time points on a fluorescent plate reader (Ab492/Em 516 nm).

Those antisense oligonucleotides that result in inhibition of binding of LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells to endothelial cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous prostate cells. Those antisense oligonucleotides that result in inhibition of endothelial cell transmigration by LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 101 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of SW620 cells, SKOV3 cells, MD-MBA-231 cells, LNCaP cells, PC3 cells, 22Rv1 cells, MDA-PCA-2b cells, and DU145 cells can be tested in a soft agar assay. Soft agar assays are conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer is formed on the bottom layer by removing cells transfected as described above from plates using 9.05% trypsin and washing twice in media. The cells are counted in a Coulter counter, and resuspended to 10⁶ per ml in media. 10 μl aliquots are placed with media in 96-well plates (to check counting with WST1), or diluted further for the soft agar assay. 2000 cells are plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidifies, 2 ml of media is dribbled on top and antisense or reverse control oligo (produced as described above) is added without delivery vehicles. Fresh media and oligos are added every 3-4 days. Colonies form in 10 days to 3 weeks. Fields of colonies are counted by eye. Wst-1 metabolism values can be used to compensate for small differences in starting cell number. Larger fields can be scanned for visual record of differences.

Those antisense oligonucleotides that result in inhibition of colony formation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit colony formation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of colony formation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit colony formation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 102 Induction of Cell Death Upon Depletion of Polypeptides by Depletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon cell death, LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells, or other cells derived from a cancer of interest, can be transfected for proliferation assays. For cytotoxic effect in the presence of cisplatin (cis), the same protocol is followed but cells are left in the presence of 2 μM drug. Each day, cytotoxicity is monitored by measuring the amount of LDH enzyme released in the medium due to membrane damage. The activity of LDH is measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). A positive control using antisense and reverse control oligonucleotides for BCL2 (a known anti-apoptotic gene) is included; loss of message for BCL2 leads to an increase in cell death compared with treatment with the control oligonucleotide (background cytotoxicity due to transfection).

Example 103 Functional Analysis of Gene Products Differentially Expressed in Cancer

The gene products of sequences of a gene differentially expressed in cancerous cells can be further analyzed to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting or inhibiting development of a metastatic phenotype. For example, the function of gene products corresponding to genes identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted or associated with a cell surface membrane, blocking antibodies can be generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype. In order to generate antibodies, a clone corresponding to a selected gene product is selected, and a sequence that represents a partial or complete coding sequence is obtained. The resulting clone is expressed, the polypeptide produced isolated, and antibodies generated. The antibodies are then combined with cells and the effect upon tumorigenesis assessed.

Where the gene product of the differentially expressed genes identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecules that inhibit or enhance function of the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limited to, those that analyze the effect of expression of the corresponding gene upon cell cycle and cell migration. Methods for performing such assays are well known in the art.

Example 104 Deposit Information

A deposit of the biological materials in the tables referenced below was made with the American Type Culture Collection, 10801 University Blvd., Manasas, Va. 20110-2209, under the provisions of the Budapest Treaty, on or before the filing date of the present application. The accession number indicated is assigned after successful viability testing, and the requisite fees were paid. Access to said cultures will be available during pendency of the patent application to one determined by the Commissioner to be entitled to such under 37 C.F.R. §1.14 and 35 U.S.C. §122. All restriction on availability of said cultures to the public will be irrevocably removed upon the granting of a patent based upon the application. Moreover, the designated deposits will be maintained for a period of thirty (30) years from the date of deposit, or for five (5) years after the last request for the deposit; or for the enforceable life of the U.S. patent, whichever is longer. Should a culture become nonviable or be inadvertently destroyed, or, in the case of plasmid-containing strains, lose its plasmid, it will be replaced with a viable culture(s) of the same taxonomic description.

These deposits are provided merely as a convenience to those of skill in the art, and are not an admission that a deposit is required. A license may be required to make, use, or sell the deposited materials, and no such license is hereby granted. The deposit below was received by the ATCC on or before the filing date of the present application.

TABLE 155 Cell Lines Deposited with ATCC ATCC CMCC Cell Line Deposit Date Accession No. Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB- May 15, 1998 CRL-12532 10583 231 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containing specific clones, were assigned an “ES” number (internal reference) and deposited with the ATCC. Table 156 below provides the ATCC Accession Nos. of the clones deposited as a library named ES217. The deposit was made on Jan. 18, 2001. Table 157 (inserted before the claims) provides the ATCC Accession Nos. of the clones deposited as libraries named ES210-ES216 on Jul. 25, 2000.

TABLE 156 Clones Deposited as Library No. ES217 with ATCC on or before Jan. 18, 2001. CloneID CMCC# ATCC# CloneID CMCC# ATCC# M00073094B:A01 5418 PTA-2918 M00073425A:H12 5418 PTA-2918 M00073096B:A12 5418 PTA-2918 M00073427B:E04 5418 PTA-2918 M00073412C:E07 5418 PTA-2918 M00073408A:D06 5418 PTA-2918 M00073408C:F06 5418 PTA-2918 M00073428D:H03 5418 PTA-2918 M00073435C:E06 5418 PTA-2918 M00073435B:E11 5418 PTA-2918 M00073403B:F06 5418 PTA-2918 M00074323D:F09 5418 PTA-2918 M00073412D:B07 5418 PTA-2918 M00074333D:A11 5418 PTA-2918 M00073421C:B07 5418 PTA-2918 M00074335A:H08 5418 PTA-2918 M00073429B:H10 5418 PTA-2918 M00074337A:G08 5418 PTA-2918 M00073412D:E02 5418 PTA-2918 M00074340B:D06 5418 PTA-2918 M00073097C:A03 5418 PTA-2918 M00074343C:A03 5418 PTA-2918 M00073403C:C10 5418 PTA-2918 M00074346A:H09 5418 PTA-2918 M00073425D:F08 5418 PTA-2918 M00074347B:F11 5418 PTA-2918 M00073403C:E11 5418 PTA-2918 M00074349A:E08 5418 PTA-2918 M00073431A:G02 5418 PTA-2918 M00074355D:H06 5418 PTA-2918 M00073412A:C03 5418 PTA-2918 M00074361C:B01 5418 PTA-2918 M00073424D:C03 5418 PTA-2918 M00074365A:E09 5418 PTA-2918 M00073430C:A01 5418 PTA-2918 M00074366A:D07 5418 PTA-2918 M00073407A:E12 5418 PTA-2918 M00074366A:H07 5418 PTA-2918 M00073412A:H09 5418 PTA-2918 M00074370D:G09 5418 PTA-2918 M00073418B:B09 5418 PTA-2918 M00074375D:E05 5418 PTA-2918 M00073403C:H09 5418 PTA-2918 M00074382D:F04 5418 PTA-2918 M00073416B:F01 5418 PTA-2918 M00074384D:G07 5418 PTA-2918 M00073425A:G10 5418 PTA-2918 M00074388B:E07 5418 PTA-2918 M00073427B:C08 5418 PTA-2918 M00074392C:D02 5418 PTA-2918 M00073430C:B02 5418 PTA-2918 M00074405B:A04 5418 PTA-2918 M00073418B:H09 5418 PTA-2918 M00074417D:F07 5418 PTA-2918 M00073423C:E01 5418 PTA-2918 M00074392D:D01 5418 PTA-2918 M00074391B:D02 5418 PTA-2918 M00074406B:F10 5418 PTA-2918 M00074390C:E04 5418 PTA-2918 M00074430D:G09 5418 PTA-2918 M00074411B:G07 5418 PTA-2918 M00074395A:B11 5418 PTA-2918 M00074415B:A01 5418 PTA-2918 M00074404B:H01 5418 PTA-2918

TABLE 157 ES No. CLONE ID ATCC# ES 210 M00073054A:A06 PTA-2376 ES 210 M00073054A:C10 PTA-2376 ES 210 M00073054B:E07 PTA-2376 ES 210 M00073054C:E02 PTA-2376 ES 210 M00073055D:E11 PTA-2376 ES 210 M00073056C:A09 PTA-2376 ES 210 M00073056C:C12 PTA-2376 ES 210 M00073057A:F09 PTA-2376 ES 210 M00073057D:A12 PTA-2376 ES 210 M00073060B:C06 PTA-2376 ES 210 M00073061B:F10 PTA-2376 ES 210 M00073061C:G08 PTA-2376 ES 210 M00073062B:D09 PTA-2376 ES 210 M00073062C:D09 PTA-2376 ES 210 M00073064C:A11 PTA-2376 ES 210 M00073064C:H09 PTA-2376 ES 210 M00073064D:B11 PTA-2376 ES 210 M00073065D:D11 PTA-2376 ES 210 M00073066B:G03 PTA-2376 ES 210 M00073066C:D02 PTA-2376 ES 210 M00073067A:E09 PTA-2376 ES 210 M00073067B:D04 PTA-2376 ES 210 M00073067D:B02 PTA-2376 ES 210 M00073069D:G03 PTA-2376 ES 210 M00073070A:B12 PTA-2376 ES 210 M00073070B:B06 PTA-2376 ES 210 M00073071D:D02 PTA-2376 ES 210 M00073072A:A10 PTA-2376 ES 210 M00073074B:G04 PTA-2376 ES 210 M00073074D:A04 PTA-2376 ES 210 M00073078B:F08 PTA-2376 ES 210 M00073080B:A07 PTA-2376 ES 210 M00073081A:F08 PTA-2376 ES 210 M00073081D:C07 PTA-2376 ES 210 M00073084C:E02 PTA-2376 ES 210 M00073085D:B01 PTA-2376 ES 210 M00073086D:B05 PTA-2376 ES 210 M00073088C:B04 PTA-2376 ES 210 M00073088D:F07 PTA-2376 ES 210 M00073091B:C04 PTA-2376 ES 210 M00073091D:B06 PTA-2376 ES 210 M00073092A:D03 PTA-2376 ES 210 M00073092D:B03 PTA-2376 ES 210 M00073094B:A01 PTA-2376 ES 210 M00073412A:C03 PTA-2376 ES 210 M00073408C:F06 PTA-2376 ES 210 M00073424D:C03 PTA-2376 ES 210 M00073403B:F06 PTA-2376 ES 210 M00073407A:E12 PTA-2376 ES 210 M00073412A:H09 PTA-2376 ES 210 M00073421C:B07 PTA-2376 ES 210 M00073416B:F01 PTA-2376 ES 210 M00073425A:G10 PTA-2376 ES 210 M00073425A:H12 PTA-2376 ES 210 M00073403C:C10 PTA-2376 ES 210 M00073428D:H03 PTA-2376 ES 210 M00073403C:E11 PTA-2376 ES 210 M00073435B:E11 PTA-2376 ES 210 M00073431A:G02 PTA-2376 ES 210 M00073412C:E07 PTA-2376 ES 210 M00073435C:E06 PTA-2376 ES 210 M00073412D:B07 PTA-2376 ES 210 M00073429B:H10 PTA-2376 ES 210 M00073403C:H09 PTA-2376 ES 210 M00073412D:E02 PTA-2376 ES 210 M00073427B:C08 PTA-2376 ES 210 M00073423C:E01 PTA-2376 ES 210 M00073427B:E04 PTA-2376 ES 210 M00073425D:F08 PTA-2376 ES 210 M00073096B:A12 PTA-2376 ES 210 M00073430C:A01 PTA-2376 ES 210 M00073418B:B09 PTA-2376 ES 210 M00073430C:B02 PTA-2376 ES 210 M00073097C:A03 PTA-2376 ES 210 M00073418B:H09 PTA-2376 ES 210 M00073408A:D06 PTA-2376 ES 210 M00073438A:A08 PTA-2376 ES 210 M00073438A:B02 PTA-2376 ES 210 M00073438D:G05 PTA-2376 ES 210 M00073442A:F07 PTA-2376 ES 210 M00073442B:D12 PTA-2376 ES 210 M00073442D:E11 PTA-2376 ES 210 M00073446C:A03 PTA-2376 ES 210 M00073447B:A03 PTA-2376 ES 210 M00073447D:F01 PTA-2376 ES 210 M00073448B:F11 PTA-2376 ES 210 M00073448B:F07 PTA-2376 ES 210 M00073453C:C09 PTA-2376 ES 210 M00073455C:G09 PTA-2376 ES 210 M00073457A:G09 PTA-2376 ES 210 M00073462C:H12 PTA-2376 ES 210 M00073462D:D12 PTA-2376 ES 210 M00073464B:E01 PTA-2376 ES 210 M00073464D:G12 PTA-2376 ES 210 M00073465A:H08 PTA-2376 ES 210 M00073469B:A09 PTA-2376 ES 210 M00073469D:A06 PTA-2376 ES 210 M00073470D:A01 PTA-2376 ES 210 M00073474A:G11 PTA-2376 ES 210 M00073474C:F08 PTA-2376 ES 210 M00073475D:E05 PTA-2376 ES 210 M00073478C:A07 PTA-2376 ES 210 M00073483B:C07 PTA-2376 ES 210 M00073484B:A05 PTA-2376 ES 210 M00073484C:B04 PTA-2376 ES 210 M00073486A:A12 PTA-2376 ES 210 M00073487A:C07 PTA-2376 ES 210 M00073489B:A07 PTA-2376 ES 210 M00073493A:E12 PTA-2376 ES 210 M00073493D:F05 PTA-2376 ES 210 M00073495B:G11 PTA-2376 ES 210 M00073497C:D03 PTA-2376 ES 210 M00073504D:F03 PTA-2376 ES 210 M00073505D:F01 PTA-2376 ES 210 M00073509B:B11 PTA-2376 ES 210 M00073509B:E03 PTA-2376 ES 210 M00073513A:G07 PTA-2376 ES 210 M00073513D:A11 PTA-2376 ES 210 M00073515A:F09 PTA-2376 ES 210 M00073517A:A06 PTA-2376 ES 210 M00073517D:F11 PTA-2376 ES 210 M00073520D:A04 PTA-2376 ES 210 M00073524A:A03 PTA-2376 ES 210 M00073524A:G05 PTA-2376 ES 210 M00073529A:F03 PTA-2376 ES 210 M00073530B:A02 PTA-2376 ES 210 M00073531B:H02 PTA-2376 ES 210 M00073531C:F12 PTA-2376 ES 210 M00073537B:A12 PTA-2376 ES 210 M00073539C:H05 PTA-2376 ES 210 M00073541B:C10 PTA-2376 ES 210 M00073547B:F04 PTA-2376 ES 210 M00073547C:D02 PTA-2376 ES 210 M00073549B:B03 PTA-2376 ES 210 M00073551B:E10 PTA-2376 ES 210 M00073552A:F06 PTA-2376 ES 210 M00073554A:C01 PTA-2376 ES 210 M00073554A:G04 PTA-2376 ES 210 M00073554B:A08 PTA-2376 ES 210 M00073554B:D11 PTA-2376 ES 210 M00073555A:B09 PTA-2376 ES 210 M00073555D:B04 PTA-2376 ES 210 M00073557A:A05 PTA-2376 ES 210 M00073558A:A02 PTA-2376 ES 210 M00073561C:A04 PTA-2376 ES 210 M00073565D:E05 PTA-2376 ES 210 M00073566A:G01 PTA-2376 ES 210 M00073568A:G06 PTA-2376 ES 210 M00073568C:G07 PTA-2376 ES 210 M00073569A:H02 PTA-2376 ES 210 M00073571A:F12 PTA-2376 ES 210 M00073575B:H12 PTA-2376 ES 210 M00073576B:E03 PTA-2376 ES 210 M00073576C:C11 PTA-2376 ES 210 M00073577B:D12 PTA-2376 ES 210 M00073579B:A04 PTA-2376 ES 210 M00073580A:D08 PTA-2376 ES 210 M00073587D:E12 PTA-2376 ES 210 M00073588B:H07 PTA-2376 ES 210 M00073590C:F07 PTA-2376 ES 210 M00073592B:D09 PTA-2376 ES 210 M00073594B:B11 PTA-2376 ES 210 M00073595D:A11 PTA-2376 ES 210 M00073598D:E11 PTA-2376 ES 210 M00073599C:E08 PTA-2376 ES 210 M00073601A:B06 PTA-2376 ES 210 M00073601A:F07 PTA-2376 ES 210 M00073601D:D08 PTA-2376 ES 210 M00073603A:F04 PTA-2376 ES 210 M00073603B:C03 PTA-2376 ES 210 M00073603C:A11 PTA-2376 ES 210 M00073603C:C02 PTA-2376 ES 210 M00073603D:E07 PTA-2376 ES 210 M00073604B:B07 PTA-2376 ES 210 M00073604B:H06 PTA-2376 ES 210 M00073604C:H09 PTA-2376 ES 210 M00073605B:F10 PTA-2376 ES 210 M00073605B:F11 PTA-2376 ES 210 M00073606D:F12 PTA-2376 ES 210 M00073610A:F06 PTA-2376 ES 210 M00073614B:A12 PTA-2376 ES 210 M00073614B:G09 PTA-2376 ES 210 M00073614C:F06 PTA-2376 ES 210 M00073615D:E03 PTA-2376 ES 210 M00073616A:F06 PTA-2376 ES 210 M00073617A:H04 PTA-2376 ES 210 M00073620A:G05 PTA-2376 ES 210 M00073621D:A04 PTA-2376 ES 210 M00073621D:D02 PTA-2376 ES 210 M00073621D:H05 PTA-2376 ES 210 M00073623D:H10 PTA-2376 ES 210 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M00074702B:F12 PTA-2381 ES 215 M00074702D:H05 PTA-2381 ES 215 M00074713B:F02 PTA-2381 ES 215 M00074716C:H07 PTA-2381 ES 215 M00074723D:C06 PTA-2381 ES 215 M00074723D:D05 PTA-2381 ES 215 M00074728C:B08 PTA-2381 ES 215 M00074730B:A04 PTA-2381 ES 215 M00074740B:F06 PTA-2381 ES 215 M00074744B:B12 PTA-2381 ES 215 M00074748C:G02 PTA-2381 ES 215 M00074752A:D08 PTA-2381 ES 215 M00074753C:E10 PTA-2381 ES 215 M00074755A:B10 PTA-2381 ES 215 M00074755A:E07 PTA-2381 ES 215 M00074765D:F06 PTA-2381 ES 215 M00074766C:F12 PTA-2381 ES 215 M00074768C:A05 PTA-2381 ES 215 M00074773C:G03 PTA-2381 ES 215 M00074774A:D03 PTA-2381 ES 215 M00074777A:E01 PTA-2381 ES 215 M00074780C:C02 PTA-2381 ES 215 M00074782A:E04 PTA-2381 ES 215 M00074808B:H02 PTA-2381 ES 215 M00074996C:D07 PTA-2381 ES 215 M00074981C:C09 PTA-2381 ES 215 M00075000A:D06 PTA-2381 ES 215 M00074805A:C12 PTA-2381 ES 215 M00074981D:A03 PTA-2381 ES 215 M00074794C:H02 PTA-2381 ES 215 M00074801C:E06 PTA-2381 ES 215 M00074821B:B03 PTA-2381 ES 215 M00074823A:E03 PTA-2381 ES 215 M00074800B:H01 PTA-2381 ES 215 M00074800D:G09 PTA-2381 ES 215 M00074812A:F03 PTA-2381 ES 215 M00074825C:E06 PTA-2381 ES 215 M00074794A:G10 PTA-2381 ES 215 M00075018A:G04 PTA-2381 ES 215 M00075020D:B04 PTA-2381 ES 215 M00075049A:C09 PTA-2381 ES 215 M00075032A:F02 PTA-2381 ES 215 M00075029B:E03 PTA-2381 ES 215 M00075069C:C01 PTA-2381 ES 215 M00075039A:E01 PTA-2381 ES 215 M00075024C:G05 PTA-2381 ES 215 M00075074D:G11 PTA-2381 ES 215 M00075011A:C11 PTA-2381 ES 215 M00075061A:B03 PTA-2381 ES 215 M00075043B:H05 PTA-2381 ES 215 M00075035C:C09 PTA-2381 ES 215 M00075045D:H03 PTA-2381 ES 215 M00075078C:A07 PTA-2381 ES 215 M00075075A:D12 PTA-2381 ES 215 M00075077C:F09 PTA-2381 ES 215 M00075026A:D11 PTA-2381 ES 215 M00075044A:C10 PTA-2381 ES 215 M00075075A:E09 PTA-2381 ES 215 M00075020C:D12 PTA-2381 ES 215 M00075117B:B06 PTA-2381 ES 215 M00075114C:G11 PTA-2381 ES 215 M00075153C:C11 PTA-2381 ES 215 M00075161A:E05 PTA-2381 ES 215 M00075126B:A06 PTA-2381 ES 215 M00075126D:H07 PTA-2381 ES 216 M00075092C:F04 PTA-2382 ES 216 M00075110C:B03 PTA-2382 ES 216 M00075132C:A03 PTA-2382 ES 216 M00075152D:C06 PTA-2382 ES 216 M00075125B:C07 PTA-2382 ES 216 M00075132C:E07 PTA-2382 ES 216 M00075160A:E04 PTA-2382 ES 216 M00075149B:A01 PTA-2382 ES 216 M00075120C:H04 PTA-2382 ES 216 M00075093B:F10 PTA-2382 ES 216 M00075102A:D02 PTA-2382 ES 216 M00075090D:B07 PTA-2382 ES 216 M00075161D:G06 PTA-2382 ES 216 M00075165B:D04 PTA-2382 ES 216 M00075174D:D06 PTA-2382 ES 216 M00075180D:F05 PTA-2382 ES 216 M00075181D:G10 PTA-2382 ES 216 M00075189C:G05 PTA-2382 ES 216 M00075199D:D11 PTA-2382 ES 216 M00075201D:A05 PTA-2382 ES 216 M00075203A:G06 PTA-2382 ES 216 M00075211D:F09 PTA-2382 ES 216 M00075221C:E02 PTA-2382 ES 216 M00075228D:G09 PTA-2382 ES 216 M00075232C:A06 PTA-2382 ES 216 M00075232D:C06 PTA-2382 ES 216 M00075234C:E06 PTA-2382 ES 216 M00075239C:D06 PTA-2382 ES 216 M00075242A:G04 PTA-2382 ES 216 M00075243D:F04 PTA-2382 ES 216 M00075245A:A06 PTA-2382 ES 216 M00075249A:B08 PTA-2382 ES 216 M00075252B:F10 PTA-2382 ES 216 M00075255A:G11 PTA-2382 ES 216 M00075259C:G02 PTA-2382 ES 216 M00075270D:A02 PTA-2382 ES 216 M00075273C:E01 PTA-2382 ES 216 M00075274B:F06 PTA-2382 ES 216 M00075275B:H07 PTA-2382 ES 216 M00075279C:E08 PTA-2382 ES 216 M00075283A:F04 PTA-2382 ES 216 M00075302B:C07 PTA-2382 ES 216 M00075305C:C07 PTA-2382 ES 216 M00075309C:A06 PTA-2382 ES 216 M00075323B:B12 PTA-2382 ES 216 M00075324B:C10 PTA-2382 ES 216 M00075324D:E02 PTA-2382 ES 216 M00075326C:B01 PTA-2382 ES 216 M00075326D:A09 PTA-2382 ES 216 M00075329B:E10 PTA-2382 ES 216 M00075330D:F11 PTA-2382 ES 216 M00075333D:B07 PTA-2382 ES 216 M00075333D:D10 PTA-2382 ES 216 M00075336B:B04 PTA-2382 ES 216 M00075344D:A08 PTA-2382 ES 216 M00075347D:D01 PTA-2382 ES 216 M00075354A:D11 PTA-2382 ES 216 M00075354A:G12 PTA-2382 ES 216 M00075354C:B12 PTA-2382 ES 216 M00075360D:D04 PTA-2382 ES 216 M00075365B:B06 PTA-2382 ES 216 M00075384A:B03 PTA-2382 ES 216 M00075389B:C06 PTA-2382 ES 216 M00075391D:D07 PTA-2382 ES 216 M00075402A:F01 PTA-2382 ES 216 M00075405B:C07 PTA-2382 ES 216 M00075405D:A10 PTA-2382 ES 216 M00075365D:B08 PTA-2382 ES 216 M00075380D:F06 PTA-2382 ES 216 M00075356D:C03 PTA-2382 ES 216 M00075352D:F09 PTA-2382 ES 216 M00075359D:E09 PTA-2382 ES 216 M00075365D:H01 PTA-2382 ES 216 M00075373C:B09 PTA-2382 ES 216 M00075378B:C07 PTA-2382 ES 216 M00075379A:E07 PTA-2382 ES 216 M00075383A:B11 PTA-2382 ES 216 M00075407A:B05 PTA-2382 ES 216 M00075409A:E04 PTA-2382 ES 216 M00075409B:G12 PTA-2382 ES 216 M00075416C:B02 PTA-2382 ES 216 M00075458B:F09 PTA-2382 ES 216 M00075464C:A07 PTA-2382 ES 216 M00075458C:F01 PTA-2382 ES 216 M00075463C:E07 PTA-2382 ES 216 M00075464C:C04 PTA-2382 ES 216 M00075448B:G11 PTA-2382 ES 216 M00075434A:D06 PTA-2382 ES 216 M00075457C:A06 PTA-2382 ES 216 M00075454C:D06 PTA-2382 ES 216 M00075460C:B06 PTA-2382 ES 216 M00075459A:C02 PTA-2382 ES 216 M00075414A:D10 PTA-2382 ES 216 M00075433A:C06 PTA-2382 ES 216 M00075505B:A04 PTA-2382 ES 216 M00075474D:B07 PTA-2382 ES 216 M00075504B:A10 PTA-2382 ES 216 M00075473C:E08 PTA-2382 ES 216 M00075499A:H02 PTA-2382 ES 216 M00075495D:D11 PTA-2382 ES 216 M00075496D:G05 PTA-2382 ES 216 M00075514A:G12 PTA-2382 ES 216 M00075495B:C12 PTA-2382 ES 216 M00075497D:H03 PTA-2382 ES 216 M00075529A:A02 PTA-2382 ES 216 M00075538C:E03 PTA-2382 ES 216 M00075544A:C03 PTA-2382 ES 216 M00075598B:A09 PTA-2382 ES 216 M00075521B:E11 PTA-2382 ES 216 M00075597C:G01 PTA-2382 ES 216 M00075584D:B05 PTA-2382 ES 216 M00075590B:G04 PTA-2382 ES 216 M00075603D:D09 PTA-2382 ES 216 M00075607B:D05 PTA-2382 ES 216 M00075609A:H06 PTA-2382 ES 216 M00075613D:F01 PTA-2382 ES 216 M00075619C:D08 PTA-2382 ES 216 M00075621A:F06 PTA-2382 ES 216 M00075639A:D12 PTA-2382

Retrieval of Individual Clones from Deposit of Pooled Clones. Where the ATCC deposit is composed of a pool of cDNA clones or a library of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones in the pool or library were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

Example 105 Detection of Genes that are Differentially Expressed in Cancer Cells

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. Table 158 (inserted prior to claims) provides information about the polynucleotides on the arrays including: (a) the “SEQ ID”, corresponding to the sequences of the Sequence Listing provided herein; (b) the “SeqName”, corresponding to a internal reference name for the sequence; (c) the “Clone Id”, corresponding to the identifier of a clone from which the sequence is derived; (d) the “Seq Type”, corresponding to the type of the sequence, either internal or consensus; (e) the “Lib. Name”, corresponding to the library from which the clone was obtained; (f) the “Cluster Id”, corresponding to an internal identifier for a set of sequences that have been grouped, i.e., clustered, based on their sequence identity, and (g), the “Length”, corresponding to the length of the sequence.

Normal and cancerous tissues were collected from patients using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001).

In general, patients (pats) had breast cancer (brst), prostate cancer (prst), colon cancer (cln). Patients with colon cancer had metastasized colon cancer (met or M), and/or primary tumors (T). Metastases of colon cancers may appear in any tissue, including bone, breast, lung, liver, brain, kidney skin, intestine, appendix, etc. In many patients, the colon cancer had metastasized to liver.

cDNA probes were prepared from total RNA isolated from the patient samples described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

In most experiments, total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from a normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

In many experiments, each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provides for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues as described. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample. In some experiments Affymetrix oligonucleotide arrays were used.

The differential expression assay was performed by mixing equal amounts of probes from matched or unmatched samples. The arrays were pre-incubated for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level of fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the matched or unmatched samples. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Results

Table 159 provides results obtained according to the methods set forth above. The results show data from several separate experiments using the same set of gene products, each identified by SEQ ID NO. The results for a particular SEQ ID are expressed as a percentage of the total number of patients in which that SEQ ID was over-expressed by at least two fold at a 95% confidence level. Accordingly, for example, SEQ ID NO:23576, the first entry, is expressed in tumor samples of 21.74% (% Brst Pats) of 23 patients (# Brst Pats) with breast cancer.

The six experiments were: 1) a comparison of the gene expression profile of cancerous breast cells to that of normal breast cells (results shown in column 3, entitled “% Brst Pats”), 2) a comparison of the gene expression profile of cancerous colon cells (primary tumor) to that of normal colon cells (results shown in column 5, entitled “% Cln Pats”), 3) a comparison of the gene expression profile of cancerous prostate cells to that of normal prostate cells (results shown in column 7, entitled “% Prst Pats”), 4) a comparison of the gene expression profile of metastasized cancerous colon cells to that of unmatched controls (i.e., a pooled sample of normal colon from many patients; results shown in column 9, entitled “% Cln Unm Met”), 5) a comparison of the gene expression profile of cancerous metastasized colon cells to that of matched (i.e. from the same patient) normal colon cells (results shown in column 11, entitled “% Cln Match met”), and 6) a comparison of the gene expression profile of cancerous metastasized colon cells to that of matched (i.e., from the same patient) colon cancer cells from a primary tumor (results shown in column 13, entitled “% Cln Match Met M/T”). Also shown in Table 159 are “SPOT ID” entries, which correspond to an internal reference identifier.

Table 160 also provides results obtained according to the methods set forth above. The results show data from several separate experiments using the same set of gene products, each identified by SEQ ID NO. Again, the results for a particular SEQ ID are expressed as a percentage of the total number of patients in which that SEQ ID was over-expressed by at least two fold at a 95% confidence level. Accordingly, for example, SEQ ID NO:23569, the first entry, is expressed in breast tumor samples of 24.44% (% Breast T/N>=2×) of 45 patients Breast T/N patients) with breast cancer.

The two experiments were: 1) a comparison of the gene expression profile of cancerous breast cells (primary tumor) to that of normal breast cells (results shown in column 3, entitled “% Breast T/N>=2×”), and 2) a comparison of the gene expression profile of cancerous colon cells (primary tumor) to that of normal colon cells (results shown in column 5, entitled “% Colon T/N>=2×”). The number of patients in the patient samples are shown in columns 4 and 6. Also known is a column entitled “PROBESET Id”, which corresponds to an internal reference identifier.

These data show that the sequences set forth in the in the sequence listing may be used to detect cancerous cells, particularly, cancerous colon, prostate, breast, and metastasized colon cells.

TABLE 158 Seq Id SeqName Clone Id Seq Type Lib Name Cluster Id Length 23569 5059.K19.GZ43_643335 M00079817D:G03 internal chiron(27) 800071 519 23570 5060.E21.GZ43_643745 M00079848A:B09 internal chiron(27) 1089548 535 23571 5060.G17.GZ43_643683 M00079856A:C12 internal chiron(27) 381805 445 23572 5061.A19.gz43_646815 M00079888C:C02 internal chiron(27) 657028 619 23573 5061.C02.gz43_646545 M00079891C:A07 internal chiron(27) 1117586 637 23574 5061.E17.gz43_646787 M00079902A:G08 internal chiron(27) 1116829 499 23575 5061.M03.gz43_646571 M00079929D:E09 internal chiron(27) 800071 557 23576 5061.N15.gz43_646764 M00079935C:A07 internal chiron(27) 398438 484 23577 5061.O18.gz43_646813 M00079939B:G07 internal chiron(27) 774843 635 23578 5061.P08.gz43_646654 M00079940C:D02 internal chiron(27) 431141 593 23579 5062.M21.GZ43_647243 M00079986C:G03 internal chiron(27) 42008 541 23580 5063.A16.GZ43_647535 M00079998A:H03 internal chiron(27) 42008 405 23581 5063.E24.GZ43_647667 M00080010A:G05 internal chiron(27) 583076 518 23582 5065.G16.GZ43_648309 M00080110D:D02 internal chiron(27) 1118029 590 23583 5065.P08.GZ43_648190 M00080136D:A10 internal chiron(27) 807607 274 23584 5184.G17.GZ43_667153 M00082049D:B06 internal chiron(28) 833900 472 23585 5185.K01.GZ43_667285 M00082099D:D04 internal chiron(28) 149149 376 23586 5185.L02.GZ43_667302 M00082103C:H08 internal chiron(28) 416674 329 23587 5185.L12.GZ43_667462 M00082104C:A10 internal chiron(28) 158514 385 23588 5186.J19.GZ43_667956 M00082152A:B06 internal chiron(29) 20806 562 23589 5186.J24.GZ43_668036 M00082152B:H01 internal chiron(29) 1110239 556 23590 5186.N17.GZ43_667928 M00082164D:A10 internal chiron(29) 410674 476 23591 5188.A08.GZ43_668539 M00082232D:E02 internal chiron(29) 1118027 546 23592 5188.G06.GZ43_668513 M00082256A:E06 internal chiron(29) 551209 610 23593 5188.H20.GZ43_668738 M00082263A:F11 internal chiron(29) 525660 636 23594 5189.O12.GZ43_669001 M00082342A:A11 internal chiron(29) 480233 606 23595 5189.P10.GZ43_668970 M00082338A:C01 internal chiron(29) 726873 441 23596 5190.E23.GZ43_669551 M00082382D:C05 internal chiron(29) 1067312 622 23597 5190.N13.GZ43_669400 M00082417A:E03 internal chiron(29) 410674 563 23598 5191.G05.GZ43_669649 M00082457B:B05 internal chiron(29) 25422 497 23599 5193.E14.GZ43_670943 M00082591A:A11 internal chiron(29) 967199 501 23600 5193.M09.GZ43_670871 M00082618A:G07 internal chiron(29) 1135172 662 23601 5193.O06.GZ43_670825 M00082628B:F05 internal chiron(29) 17174 524 23602 5195.C15.GZ43_671725 M00082718D:E03 internal chiron(29) 400889 613 23603 5195.E15.GZ43_671727 M00082729C:C08 internal chiron(29) 1193184 602 23604 5234.B09.GZ43_673764 M00083298C:G12 internal chiron(29) 1119238 497 23605 5234.H23.GZ43_673994 M00083332C:D11 internal chiron(29) 25422 644 23606 5234.O05.GZ43_673713 M00083289D:G08 internal chiron(29) 583076 624 23607 5236.J03.GZ43_674444 M00083437D:E04 internal chiron(29) 606382 426 23608 5236.O18.GZ43_674689 M00083459D:B01 internal chiron(29) 378206 580 23609 5238.A24.GZ43_675194 M00083524A:G10 internal chiron(29) 726873 473 23610 Clu1052434.con_1 consensus 1052434 352 23611 Clu1052615.con_1 consensus 1052615 439 23612 Clu1053096.con_1 consensus 1053096 529 23613 Clu1058283.con_1 consensus 1058283 824 23614 Clu1067312.con_1 consensus 1067312 691 23615 Clu1069553.con_2 consensus 1069553 576 23616 Clu1080217.con_1 consensus 1080217 547 23617 Clu1081611.con_1 consensus 1081611 399 23618 Clu1082099.con_1 consensus 1082099 440 23619 Clu1082189.con_1 consensus 1082189 470 23620 Clu1082283.con_2 consensus 1082283 529 23621 Clu1082399.con_1 consensus 1082399 534 23622 Clu1082489.con_1 consensus 1082489 355 23623 Clu1082628.con_1 consensus 1082628 554 23624 Clu1082731.con_1 consensus 1082731 289 23625 Clu1083148.con_1 consensus 1083148 757 23626 Clu1083900.con_1 consensus 1083900 502 23627 Clu1089548.con_1 consensus 1089548 667 23628 Clu1116089.con_1 consensus 1116089 369 23629 Clu1116829.con_1 consensus 1116829 586 23630 Clu1116919.con_1 consensus 1116919 806 23631 Clu1116945.con_1 consensus 1116945 566 23632 Clu1117021.con_1 consensus 1117021 978 23633 Clu1117079.con_1 consensus 1117079 543 23634 Clu1117586.con_1 consensus 1117586 678 23635 Clu1117625.con_1 consensus 1117625 277 23636 Clu1118027.con_1 consensus 1118027 590 23637 Clu1118511.con_1 consensus 1118511 815 23638 Clu1119238.con_1 consensus 1119238 588 23639 Clu1119896.con_1 consensus 1119896 386 23640 Clu1126645.con_1 consensus 1126645 509 23641 Clu1132147.con_1 consensus 1132147 583 23642 Clu1139444.con_1 consensus 1139444 677 23643 Clu1139499.con_1 consensus 1139499 498 23644 Clu1140276.con_1 consensus 1140276 485 23645 Clu1140367.con_2 consensus 1140367 424 23646 Clu1140589.con_1 consensus 1140589 821 23647 Clu1141931.con_1 consensus 1141931 565 23648 Clu1193580.con_1 consensus 1193580 629 23649 Clu1193799.con_1 consensus 1193799 733 23650 Clu1193833.con_2 consensus 1193833 566 23651 Clu149149.con_2 consensus 149149 564 23652 Clu19522.con_1 consensus 19522 809 23653 Clu21222.con_1 consensus 21222 774 23654 Clu25422.con_1 consensus 25422 766 23655 Clu258716.con_1 consensus 258716 872 23656 Clu374843.con_1 consensus 374843 656 23657 Clu377719.con_1 consensus 377719 1382 23658 Clu377939.con_1 consensus 377939 1152 23659 Clu378206.con_1 consensus 378206 584 23660 Clu398438.con_1 consensus 398438 736 23661 Clu400889.con_1 consensus 400889 741 23662 Clu403038.con_1 consensus 403038 773 23663 Clu410674.con_1 consensus 410674 822 23664 Clu411226.con_1 consensus 411226 907 23665 Clu413700.con_1 consensus 413700 951 23666 Clu416674.con_1 consensus 416674 766 23667 Clu42008.con_1 consensus 42008 1057 23668 Clu451094.con_1 consensus 451094 443 23669 Clu451310.con_1 consensus 451310 484 23670 Clu451496.con_2 consensus 451496 1000 23671 Clu455524.con_1 consensus 455524 363 23672 Clu456861.con_1 consensus 456861 525 23673 Clu480233.con_2 consensus 480233 622 23674 Clu512287.con_2 consensus 512287 491 23675 Clu525660.con_1 consensus 525660 650 23676 Clu532281.con_1 consensus 532281 636 23677 Clu552745.con_1 consensus 552745 373 23678 Clu554732.con_1 consensus 554732 474 23679 Clu556189.con_1 consensus 556189 698 23680 Clu579754.con_1 consensus 579754 653 23681 Clu593641.con_1 consensus 593641 890 23682 Clu643318.con_1 consensus 643318 498 23683 Clu657028.con_1 consensus 657028 807 23684 5072.K10.GZ43_650909 M00080470D:C10 internal chiron(27) 410674 557 23685 5072.P20.GZ43_651074 M00080489D:G10 internal chiron(27) 856078 489 23686 5073.C07.GZ43_651237 M00080495C:B05 internal chiron(27) 533096 590 23687 5073.D08.GZ43_651254 M00080498D:E12 internal chiron(27) 1067312 578 23688 5073.J20.GZ43_651452 M00080515D:H06 internal chiron(27) 400889 504 23689 5074.H06.GZ43_651610 M00080558A:G02 internal chiron(27) 618862 544 23690 5074.J21.GZ43_651852 M00080569D:E04 internal chiron(27) 1118511 573 23691 5075.A20.GZ43_652211 M00080608C:E03 internal chiron(27) 1117586 584 23692 5075.M03.GZ43_651951 M00080642C:G04 internal chiron(27) 723800 577 23693 5076.B04.GZ43_652340 M00080658D:B05 internal chiron(27) 1083148 615 23694 5076.H07.GZ43_652394 M00080683A:F07 internal chiron(27) 168428 548 23695 5076.P22.GZ43_652642 M00080721A:B11 internal chiron(27) 1118511 625 23696 5097.D01.GZ43_652699 M00080728C:A06 internal chiron(27) 1116829 533 23697 5097.M04.GZ43_652756 M00080734D:A04 internal chiron(27) 613936 565 23698 5097.P10.GZ43_652855 M00080747A:B06 internal chiron(27) 831704 195 23699 5098.C09.GZ43_653210 M00080839A:C05 internal chiron(27) 1117079 536 23700 5098.E12.GZ43_653260 M00080849C:A06 internal chiron(27) 666002 500 23701 5130.F02.GZ43_659697 M00081454C:B02 internal chiron(28) 833900 670 23702 5130.O17.GZ43_659946 M00081478A:A12 internal chiron(28) 520284 542 23703 5130.P09.GZ43_659819 M00081479D:H03 internal chiron(28) 1138736 621 23704 5131.N24.GZ43_660441 M00081516A:F04 internal chiron(28) 469630 455 23705 5132.D09.GZ43_660575 M00081524D:E12 internal chiron(28) 411226 558 23706 5133.B13.GZ43_661021 M00081558D:C08 internal chiron(28) 532281 415 23707 5133.G11.GZ43_660994 M00081568D:D02 internal chiron(28) 89239 557 23708 5133.J24.GZ43_661205 M00081574B:A04 internal chiron(28) 644751 550 23709 5133.N07.GZ43_660937 M00081580D:E03 internal chiron(28) 526675 603 23710 5134.J13.GZ43_661413 M00081607C:D05 internal chiron(28) 964646 489 23711 5134.N11.GZ43_661385 M00081616B:H01 internal chiron(28) 454662 397 23712 5134.O05.GZ43_661290 M00081618A:B06 internal chiron(28) 31223 491 23713 5136.B15.GZ43_662228 M00081661D:A10 internal chiron(28) 1069553 413 23714 5136.H18.GZ43_662282 M00081678A:A12 internal chiron(28) 512287 487 23715 5136.K03.GZ43_662045 M00081683B:C09 internal chiron(28) 532281 626 23716 5136.K16.GZ43_662253 M00081684B:C10 internal chiron(28) 378206 509 23717 5136.P01.GZ43_662018 M00081693B:F12 internal chiron(28) 89239 495 23718 Clu666002.con_1 consensus 666002 530 23719 Clu685022.con_1 consensus 685022 599 23720 Clu715440.con_2 consensus 715440 611 23721 Clu726873.con_1 consensus 726873 687 23722 Clu775364.con_1 consensus 775364 601 23723 Clu800071.con_1 consensus 800071 685 23724 Clu807607.con_1 consensus 807607 562 23725 Clu954632.con_1 consensus 954632 292 23726 Clu964646.con_1 consensus 964646 526 23727 Clu982132.con_1 consensus 982132 987 23728 5066.J20.GZ43_648760 M00080164D:H10 internal chiron(27) 618862 344 23729 5066.N15.GZ43_648684 M00080179D:G07 internal chiron(27) 1083148 259 23730 5066.O24.GZ43_648829 M00080184B:C10 internal chiron(27) 19522 303 23731 5069.A20.GZ43_649907 M00080285A:E12 internal chiron(27) 1119238 588 23732 5069.I09.GZ43_649739 M00080317A:G01 internal chiron(27) 1117079 537 23733 5069.M04.GZ43_649663 M00080331C:D09 internal chiron(27) 685022 592 23734 5070.G07.GZ43_650089 M00080362D:F11 internal chiron(27) 258716 520 23735 5071.H06.GZ43_650458 M00080407D:G09 internal chiron(27) 386188 216 23736 5071.J11.GZ43_650540 M00080413D:D07 internal chiron(27) 1117021 569 23737 5098.I02.GZ43_653104 M00080819B:G07 internal chiron(27) 398438 459 23738 5101.B10.GZ43_654377 M00081030A:D09 internal chiron(28) 1139444 562 23739 5102.A22.GZ43_654952 M00081093B:C04 internal chiron(28) 1139037 467 23740 5103.J01.GZ43_655009 M00081178D:C12 internal chiron(28) 643318 455 23741 5104.I13.GZ43_655584 M00081223D:D06 internal chiron(28) 558521 637 23742 5104.O16.GZ43_655638 M00081228B:C04 internal chiron(28) 1139048 327 23743 5105.P13.GZ43_655975 M00081288D:G08 internal chiron(28) 1140612 542 23744 5106.I21.GZ43_656480 M00081313D:B12 internal chiron(28) 643318 498 23745 5106.M18.GZ43_656436 M00081323D:C07 internal chiron(28) 964646 429 23746 5127.A11.GZ43_658684 M00081333C:A04 internal chiron(28) 89239 438 23747 5127.E23.GZ43_658880 M00081344A:C10 internal chiron(28) 715440 610 23748 5128.J24.GZ43_659285 M00081385B:D11 internal chiron(28) 848070 546 23749 5128.L10.GZ43_659063 M00081388B:A12 internal chiron(28) 1138291 483 23750 5129.J16.GZ43_659541 M00081428A:B10 internal chiron(28) 1141931 482 23751 5129.P04.GZ43_659355 M00081441D:F01 internal chiron(28) 1117586 496 23752 5130.C16.GZ43_659918 M00081450C:E09 internal chiron(28) 523988 573 23753 5130.D14.GZ43_659887 M00081452A:G03 internal chiron(28) 631472 408 23754 5177.B11.GZ43_664364 M00081717D:A10 internal chiron(28) 411226 366 23755 5177.D13.GZ43_664398 M00081723A:C02 internal chiron(28) 1139444 493 23756 5177.H05.GZ43_664274 M00081705D:B04 internal chiron(28) 964646 406 23757 5178.G24.GZ43_664961 M00081767C:G04 internal chiron(28) 374843 614 23758 5178.N01.GZ43_664600 M00081780B:F07 internal chiron(28) 884215 516 23759 5179.I06.GZ43_665059 M00081806D:C10 internal chiron(28) 685022 593 23760 5179.L07.GZ43_665078 M00081812D:A11 internal chiron(28) 9087 444 23761 5181.B17.GZ43_665996 M00081873D:A03 internal chiron(28) 1117625 129 23762 5181.C18.GZ43_666013 M00081878B:G04 internal chiron(28) 512287 434 23763 5181.O23.GZ43_666105 M00081914C:H06 internal chiron(28) 1140589 509 23764 5182.L02.GZ43_666150 M00081924D:E02 internal chiron(28) 532281 627 23765 5182.M10.GZ43_666279 M00081938B:D03 internal chiron(28) 480233 618 23766 5183.J06.GZ43_666596 M00081995C:C03 internal chiron(28) 867272 521 23767 5183.K20.GZ43_666821 M00081999D:H07 internal chiron(28) 416674 394

TABLE 159 # Cln # Cln # % Cln Unm % Cln Match % Cln % Cln SPOT % Brst Brst % Cln # Cln % Prst # Prst Unm Met Match Met M/N Match Match SEQ ID ID Pats Pats Pats Pats Pats Pats Met Pats Met Pats Met M/T Met M/T 23576 62615 21.74 23 15.79 19 97 5.56 18 5.56 18 23576 62615 21.74 23 15.79 19 97 5.56 18 5.56 18 23577 42089 13.04 23 23.68 76 9.80 102 3.03 33 8.33 36 36 23579 10592 23 24.68 77 102 12.12 33 16.67 36 36 23579 10592 23 24.68 77 102 12.12 33 16.67 36 36 23580 10592 23 24.68 77 102 12.12 33 16.67 36 36 23581 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23584 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23585 62233 30.43 23 31.58 19 7.22 97 16.67 18 5.56 18 23585 53177 30.43 23 20.00 75 7.84 102 30.30 33 28.57 35 5.56 36 23585 62233 30.43 23 31.58 19 7.22 97 16.67 18 5.56 18 23586 61035 17.39 23 15.79 19 22.68 97 5.56 18 18 23586 61035 17.39 23 15.79 19 22.68 97 5.56 18 18 23588 65344 21.74 23 31.58 19 97 16.67 18 18 23588 65344 21.74 23 31.58 19 97 16.67 18 18 23588 65344 21.74 23 31.58 19 97 16.67 18 18 23588 61198 21.74 23 10.53 19 2.06 97 11.11 18 18 23588 61198 21.74 23 10.53 19 2.06 97 11.11 18 18 23594 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23594 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23596 62019 30.43 23 19 97 18 18 23596 62019 30.43 23 19 97 18 18 23598 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23598 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23599 3835 8 20.00 35 2.94 34 23.33 30 14.29 7 7 23601 3835 8 20.00 35 2.94 34 23.33 30 14.29 7 7 23602 35056 4.35 23 30.67 75 1.96 102 54.55 33 36.11 36 36 23603 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23603 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23605 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23605 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23605 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23605 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23606 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23607 65474 21.74 23 78.95 19 12.37 97 66.67 18 18 23607 65474 21.74 23 78.95 19 12.37 97 66.67 18 18 23614 62019 30.43 23 19 97 18 18 23614 62019 30.43 23 19 97 18 18 23615 51042 26.09 23 2.67 75 3.92 102 3.03 33 35 36 23615 51042 26.09 23 2.67 75 3.92 102 3.03 33 35 36 23630 37575 4.35 23 22.67 75 14.71 102 33 36.11 36 5.56 36 23630 37575 4.35 23 22.67 75 14.71 102 33 36.11 36 5.56 36 23646 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23646 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23646 46009 23 30.26 76 8.82 102 21.21 33 51.43 35 5.56 36 23646 4066 8 28.57 35 11.76 34 26.67 30 42.86 7 7 23646 4066 8 28.57 35 11.76 34 26.67 30 42.86 7 7 23646 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23651 53177 30.43 23 20.00 75 7.84 102 30.30 33 28.57 35 5.56 36 23651 62233 30.43 23 31.58 19 7.22 97 16.67 18 5.56 18 23651 62233 30.43 23 31.58 19 7.22 97 16.67 18 5.56 18 23651 54930 21.74 23 16.00 75 9.80 102 21.21 33 25.71 35 36 23654 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23654 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23654 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23654 61000 26.09 23 5.26 19 32.99 97 18 16.67 18 23656 60741 23 47.37 19 22.68 97 33.33 18 18 23660 62615 21.74 23 15.79 19 97 5.56 18 5.56 18 23660 62615 21.74 23 15.79 19 97 5.56 18 5.56 18 23661 35056 4.35 23 30.67 75 1.96 102 54.55 33 36.11 36 36 23666 61035 17.39 23 15.79 19 22.68 97 5.56 18 18 23666 61035 17.39 23 15.79 19 22.68 97 5.56 18 18 23667 10592 23 24.68 77 102 12.12 33 16.67 36 36 23667 10592 23 24.68 77 102 12.12 33 16.67 36 36 23673 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23673 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23676 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23679 52789 17.39 23 6.67 75 4.90 102 21.21 33 8.57 35 36 23681 35754 23 20.00 75 2.94 102 30.30 33 36.11 36 36 23681 36946 23 24.00 75 1.96 102 18.18 33 30.56 36 2.78 36 23681 35754 23 20.00 75 2.94 102 30.30 33 36.11 36 36 23681 36946 23 24.00 75 1.96 102 18.18 33 30.56 36 2.78 36 23681 34559 23 30.67 75 1.96 102 30.30 33 33.33 36 5.56 36 23687 62019 30.43 23 19 97 18 18 23687 62019 30.43 23 19 97 18 18 23688 35056 4.35 23 30.67 75 1.96 102 54.55 33 36.11 36 36 23698 65508 30.43 23 19 12.37 97 18 18 23698 35939 26.09 23 75 9.80 102 33 8.33 36 36 23698 55189 26.09 23 5.26 19 8.16 98 17 18 23698 65508 30.43 23 19 12.37 97 18 18 23698 54046 26.09 23 75 14.71 102 3.03 33 35 2.78 36 23700 62439 21.74 23 19 97 18 18 23700 62439 21.74 23 19 97 18 18 23701 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23702 61479 26.09 23 63.16 19 3.09 97 61.11 18 18 23702 33688 17.39 23 21.05 76 0.98 102 15.15 33 34.29 35 2.78 36 23702 54586 17.39 23 12.00 75 102 6.06 33 31.43 35 36 23702 51783 21.74 23 38.67 75 1.96 102 30.30 33 57.14 35 36 23702 17831 22.22 18 39.02 41 1.56 64 40.00 30 54.55 11 9.09 11 23704 60458 4.35 23 57.89 19 25.77 97 61.11 18 18 23704 60458 4.35 23 57.89 19 25.77 97 61.11 18 18 23704 60458 4.35 23 57.89 19 25.77 97 61.11 18 18 23704 60458 4.35 23 57.89 19 25.77 97 61.11 18 18 23706 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23707 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23712 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23713 51042 26.09 23 2.67 75 3.92 102 3.03 33 35 36 23713 51042 26.09 23 2.67 75 3.92 102 3.03 33 35 36 23715 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23717 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23718 62439 21.74 23 19 97 18 18 23718 62439 21.74 23 19 97 18 18 23719 9191 21.74 23 55.84 77 3.92 102 39.39 33 58.33 36 11.11 36 23727 11583 21.74 23 44.16 77 1.96 102 27.27 33 66.67 36 2.78 36 23727 37868 26.09 23 49.33 75 4.90 102 36.36 33 55.56 36 5.56 36 23727 37868 26.09 23 49.33 75 4.90 102 36.36 33 55.56 36 5.56 36 23727 35285 30.43 23 56.00 75 2.94 102 33.33 33 52.78 36 8.33 36 23727 35285 30.43 23 56.00 75 2.94 102 33.33 33 52.78 36 8.33 36 23727 11583 21.74 23 44.16 77 1.96 102 27.27 33 66.67 36 2.78 36 23733 9191 21.74 23 55.84 77 3.92 102 39.39 33 58.33 36 11.11 36 23737 62615 21.74 23 15.79 19 97 5.56 18 5.56 18 23737 62615 21.74 23 15.79 19 97 5.56 18 5.56 18 23741 63119 26.09 23 19 1.03 97 18 22.22 18 23741 63119 26.09 23 19 1.03 97 18 22.22 18 23746 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23749 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23757 60741 23 47.37 19 22.68 97 33.33 18 18 23759 9191 21.74 23 55.84 77 3.92 102 39.39 33 58.33 36 11.11 36 23761 64570 4.35 23 19 20.62 97 5.56 18 16.67 18 23761 64570 4.35 23 19 20.62 97 5.56 18 16.67 18 23763 4066 8 28.57 35 11.76 34 26.67 30 42.86 7 7 23763 4066 8 28.57 35 11.76 34 26.67 30 42.86 7 7 23763 46009 23 30.26 76 8.82 102 21.21 33 51.43 35 5.56 36 23763 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23763 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23763 1542 8 54.29 35 20.59 34 40.00 30 57.14 7 7 23764 24511 23 9.38 64 4.00 100 24.24 33 26.09 23 4.35 23 23765 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23765 24403 8.70 23 40.63 64 4.00 100 48.48 33 43.48 23 23 23767 61035 17.39 23 15.79 19 22.68 97 5.56 18 18 23767 61035 17.39 23 15.79 19 22.68 97 5.56 18 18

TABLE 160 Colon PROBESET % Breast Breast T/N % Colon M/N Seq Id Id T/N >= 2x Patients M/N >= 2x Patients 23569 3323 24.44 45 44.83 29 23570 47141 100.00 12 100.00 11 23571 22807 20.83 48 100.00 23 23572 47166 100.00 3 8.33 12 23573 47170 100.00 7 100.00 10 23573 47170 100.00 7 100.00 10 23573 47170 100.00 7 100.00 10 23574 54439 100.00 1 15 23575 3323 24.44 45 44.83 29 23578 47204 100.00 21 27 23581 7337 16.67 18 100.00 14 23582 9348 52.27 44 9.52 21 23583 55586 100.00 4 100.00 4 23584 7337 16.67 18 100.00 14 23587 48770 100.00 3 21.43 28 23589 26738 56.00 25 23589 26738 56.00 25 23589 26738 56.00 25 23589 26738 56.00 25 23590 48850 4.00 25 50.00 4 23591 35733 100.00 1 77.27 22 23591 35733 100.00 1 77.27 22 23592 25507 100.00 22 18.52 27 23593 48810 100.00 4 28 23595 35493 48.00 50 3.45 29 23595 35493 48.00 50 3.45 29 23596 55391 16.28 43 100.00 1 23597 48850 4.00 25 50.00 4 23600 48901 10.00 20 100.00 11 23600 48901 10.00 20 100.00 11 23604 47395 100.00 1 23606 7337 16.67 18 100.00 14 23608 35013 44 100.00 10 23608 35013 44 100.00 10 23609 35493 48.00 50 3.45 29 23609 35493 48.00 50 3.45 29 23610 15407 100.00 24 3.85 26 23610 15407 100.00 24 3.85 26 23610 15407 100.00 24 3.85 26 23610 15407 100.00 24 3.85 26 23611 15407 100.00 24 3.85 26 23611 15407 100.00 24 3.85 26 23611 15407 100.00 24 3.85 26 23611 15407 100.00 24 3.85 26 23612 15407 100.00 24 3.85 26 23612 15407 100.00 24 3.85 26 23612 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23613 15407 100.00 24 3.85 26 23614 55391 16.28 43 100.00 1 23616 15407 100.00 24 3.85 26 23616 15407 100.00 24 3.85 26 23616 15407 100.00 24 3.85 26 23616 15407 100.00 24 3.85 26 23617 15407 100.00 24 3.85 26 23617 15407 100.00 24 3.85 26 23617 15407 100.00 24 3.85 26 23618 15407 100.00 24 3.85 26 23618 15407 100.00 24 3.85 26 23618 15407 100.00 24 3.85 26 23618 15407 100.00 24 3.85 26 23618 15407 100.00 24 3.85 26 23619 15407 100.00 24 3.85 26 23619 15407 100.00 24 3.85 26 23619 15407 100.00 24 3.85 26 23619 15407 100.00 24 3.85 26 23619 15407 100.00 24 3.85 26 23620 15407 100.00 24 3.85 26 23620 15407 100.00 24 3.85 26 23620 15407 100.00 24 3.85 26 23620 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23621 15407 100.00 24 3.85 26 23622 15407 100.00 24 3.85 26 23622 15407 100.00 24 3.85 26 23623 15407 100.00 24 3.85 26 23623 15407 100.00 24 3.85 26 23623 15407 100.00 24 3.85 26 23623 15407 100.00 24 3.85 26 23623 15407 100.00 24 3.85 26 23624 15407 100.00 24 3.85 26 23624 15407 100.00 24 3.85 26 23624 15407 100.00 24 3.85 26 23624 15407 100.00 24 3.85 26 23625 14582 100.00 5 42.86 28 23625 14582 100.00 5 42.86 28 23626 15407 100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23626 15407 100.00 24 3.85 26 23627 47141 100.00 12 100.00 11 23628 15407 100.00 24 3.85 26 23628 15407 100.00 24 3.85 26 23628 15407 100.00 24 3.85 26 23628 15407 100.00 24 3.85 26 23629 54439 100.00 1 15 23631 15407 100.00 24 3.85 26 23631 15407 100.00 24 3.85 26 23631 15407 100.00 24 3.85 26 23631 15407 100.00 24 3.85 26 23631 15407 100.00 24 3.85 26 23632 3323 24.44 45 44.83 29 23633 47409 50.00 4 23634 47170 100.00 7 100.00 10 23634 47170 100.00 7 100.00 10 23634 47170 100.00 7 100.00 10 23635 15407 100.00 24 3.85 26 23635 15407 100.00 24 3.85 26 23635 15407 100.00 24 3.85 26 23635 15407 100.00 24 3.85 26 23635 15407 100.00 24 3.85 26 23635 15407 100.00 24 3.85 26 23636 35733 100.00 1 77.27 22 23636 35733 100.00 1 77.27 22 23637 47589 46.51 43 9.09 22 23638 47395 100.00 1 23639 15407 100.00 24 3.85 26 23639 15407 100.00 24 3.85 26 23639 15407 100.00 24 3.85 26 23639 15407 100.00 24 3.85 26 23640 15407 100.00 24 3.85 26 23640 15407 100.00 24 3.85 26 23640 15407 100.00 24 3.85 26 23640 15407 100.00 24 3.85 26 23641 15407 100.00 24 3.85 26 23641 15407 100.00 24 3.85 26 23641 15407 100.00 24 3.85 26 23641 15407 100.00 24 3.85 26 23642 52781 100.00 19 27 23643 15407 100.00 24 3.85 26 23643 15407 100.00 24 3.85 26 23643 15407 100.00 24 3.85 26 23643 15407 100.00 24 3.85 26 23643 15407 100.00 24 3.85 26 23644 15407 100.00 24 3.85 26 23644 15407 100.00 24 3.85 26 23644 15407 100.00 24 3.85 26 23644 15407 100.00 24 3.85 26 23645 15407 100.00 24 3.85 26 23645 15407 100.00 24 3.85 26 23645 15407 100.00 24 3.85 26 23647 22180 100.00 5 23647 22180 100.00 5 23648 15407 100.00 24 3.85 26 23648 15407 100.00 24 3.85 26 23648 15407 100.00 24 3.85 26 23648 15407 100.00 24 3.85 26 23648 15407 100.00 24 3.85 26 23648 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23649 15407 100.00 24 3.85 26 23650 15407 100.00 24 3.85 26 23650 15407 100.00 24 3.85 26 23650 15407 100.00 24 3.85 26 23650 15407 100.00 24 3.85 26 23652 26408 16.00 50 56.00 25 23652 26408 16.00 50 56.00 25 23653 19860 16.33 49 65.52 29 23655 47444 44 74.07 27 23657 38650 24.14 29 100.00 1 23657 38650 24.14 29 100.00 1 23658 29692 100.00 12 16 23658 29692 100.00 12 16 23659 35013 44 100.00 10 23659 35013 44 100.00 10 23662 47338 100.00 2 25.00 4 23663 48850 4.00 25 50.00 4 23664 54961 100.00 28 7.14 28 23665 26394 68.00 50 34.48 29 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23668 15407 100.00 24 3.85 26 23669 15407 100.00 24 3.85 26 23669 15407 100.00 24 3.85 26 23669 15407 100.00 24 3.85 26 23670 15407 100.00 24 3.85 26 23670 15407 100.00 24 3.85 26 23671 15407 100.00 24 3.85 26 23671 15407 100.00 24 3.85 26 23671 15407 100.00 24 3.85 26 23672 15407 100.00 24 3.85 26 23672 15407 100.00 24 3.85 26 23672 15407 100.00 24 3.85 26 23672 15407 100.00 24 3.85 26 23672 15407 100.00 24 3.85 26 23674 55038 100.00 8 6.67 15 23675 48810 100.00 4 28 23677 15407 100.00 24 3.85 26 23677 15407 100.00 24 3.85 26 23677 15407 100.00 24 3.85 26 23678 15407 100.00 24 3.85 26 23678 15407 100.00 24 3.85 26 23678 15407 100.00 24 3.85 26 23678 15407 100.00 24 3.85 26 23680 47668 39.53 43 50.00 28 23682 47958 42 77.78 27 23683 47166 100.00 3 8.33 12 23718 52866 18.18 44 87.50 8 23719 3323 24.44 45 44.83 29 23720 48070 100.00 2 16.67 18 23721 35493 48.00 50 3.45 29 23721 35493 48.00 50 3.45 29 23722 15407 100.00 24 3.85 26 23722 15407 100.00 24 3.85 26 23722 15407 100.00 24 3.85 26 23722 15407 100.00 24 3.85 26 23722 15407 100.00 24 3.85 26 23723 3323 24.44 45 44.83 29 23724 55586 100.00 4 100.00 4 23725 15407 100.00 24 3.85 26 23725 15407 100.00 24 3.85 26 23725 15407 100.00 24 3.85 26 23725 15407 100.00 24 3.85 26 23725 15407 100.00 24 3.85 26 23726 48510 100.00 6 3.57 28 23728 28027 26.09 46 4.35 23 23728 28027 26.09 46 4.35 23 23729 14582 100.00 5 42.86 28 23729 14582 100.00 5 42.86 28 23730 26408 16.00 50 56.00 25 23731 47395 100.00 1 23732 47409 50.00 4 23733 3323 24.44 45 44.83 29 23734 47444 44 74.07 27 23735 22963 100.00 1 23736 3323 24.44 45 44.83 29 23684 48850 4.00 25 50.00 4 23685 20206 100.00 4 22 23686 35206 47 100.00 2 23687 55391 16.28 43 100.00 1 23689 28027 26.09 46 4.35 23 23689 28027 26.09 46 4.35 23 23689 28027 26.09 46 4.35 23 23690 47589 46.51 43 9.09 22 23691 47170 100.00 7 100.00 10 23691 47170 100.00 7 100.00 10 23692 47615 34.09 44 100.00 17 23693 14582 100.00 5 42.86 28 23693 14582 100.00 5 42.86 28 23694 47644 100.00 6 25.93 27 23695 47589 46.51 43 9.09 22 23696 54439 100.00 1 15 23697 47682 31.58 19 50.00 16 23697 47682 31.58 19 50.00 16 23699 47409 50.00 4 23700 52866 18.18 44 87.50 8 23738 52781 100.00 19 27 23739 3308 50.00 16 29 23740 47958 42 77.78 27 23742 47958 42 77.78 27 23743 9939 100.00 2 29 23744 47958 42 77.78 27 23745 48510 100.00 6 3.57 28 23746 7337 16.67 18 100.00 14 23747 48070 100.00 2 16.67 18 23748 48510 100.00 6 3.57 28 23749 7337 16.67 18 100.00 14 23750 22180 100.00 5 23750 22180 100.00 5 23751 47170 100.00 7 100.00 10 23751 47170 100.00 7 100.00 10 23752 35682 100.00 6 29 23753 48220 100.00 6 3.57 28 23701 7337 16.67 18 100.00 14 23703 48261 100.00 3 100.00 1 23705 54961 100.00 28 7.14 28 23707 7337 16.67 18 100.00 14 23708 54795 100.00 1 100.00 1 23709 52709 100.00 4 100.00 4 23710 48510 100.00 6 3.57 28 23711 4308 100.00 2 23714 55038 100.00 8 6.67 15 23716 35013 44 100.00 10 23716 35013 44 100.00 10 23754 54961 100.00 28 7.14 28 23755 52781 100.00 19 27 23756 48510 100.00 6 3.57 28 23758 19201 30 44.44 9 23759 3323 24.44 45 44.83 29 23760 48580 100.00 4 26 23762 55038 100.00 8 6.67 15 23766 48716 100.00 6

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. 

1. A method for assessing the risk that a human patient has colon cancer comprising: a) determining a level of a nucleic acid and a level of at least one molecular marker gene in a patient sample comprising human colon cells, said nucleic acid comprising the nucleotide sequence of SEQ ID NO: 23702; b) comparing said level of the nucleic acid in (a) to a control level of the nucleic acid; and c) comparing said level of the at least one molecular marker gene in (a) to a control level of the at least one molecular marker gene; wherein at least a two-fold increase between the level of the nucleic acid in (a) and the control level of the nucleic acid, and a change in levels of expression between the level of the at least one molecular marker gene in (a) and the control level of the at least one molecular marker gene indicate that there is an increased risk that the patient has colon cancer.
 2. The method of claim 1 wherein the at least a two-fold increase is at least a five-fold increase compared with the control level of the nucleic acid.
 3. The method of claim 1, wherein said determining step uses a polymerase chain reaction.
 4. The method of claim 1, wherein said determining step uses hybridization.
 5. The method of claim 1, wherein said patient sample is a sample of tissue suspected of having cancerous cells.
 6. A method for assessing the risk that a human patient has breast cancer comprising: a) determining a level of a nucleic acid and a level of at least one molecular marker gene in a patient sample comprising human breast cells, said nucleic acid comprising the nucleotide sequence of SEQ ID NO: 23702; b) comparing said level of the nucleic acid in (a) to a control level of the nucleic acid; and c) comparing said level of the at least one molecular marker gene in (a) to a control level of the at least one molecular marker gene; wherein at least a two-fold increase between the level of the nucleic acid in (a) and the control level of the nucleic acid, and a change in levels of expression between the level of the at least one molecular marker gene in (a) and the control level of the at least one molecular marker gene indicate that there is an increased risk that the patient has breast cancer.
 7. The method of claim 6 wherein the at least a two-fold increase is at least a five-fold increase compared with the control level of the nucleic acid.
 8. The method of claim 6, wherein said determining step uses a polymerase chain reaction.
 9. The method of claim 6, wherein said determining step uses hybridization.
 10. The method of claim 6, wherein said patient sample is a sample of tissue suspected of having cancerous cells. 